A Clinical Trial Comparing the Tolerability of Etravirine to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Treatment-naive HIV-1 Infected Patients (SENSE)

• Antiviral Activity of ETR vs. EFV [ Time Frame: between baseline and week 48 ] [ Designated as safety issue: No ]
  The proportion of patients with confirmed plasma viral load <50 copies/mL at Week 48 as assessed by Time to Loss of Virologic Response (TLOVR)
• Antiviral Activity of ETR vs. EFV [ Time Frame: between baseline and week 48 ] [ Designated as safety issue: No ]
  The proportion of patients with confirmed plasma viral load <200 copies/mL at Week 48 as assessed by Time to Loss of Virologic Response (TLOVR)
• Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score [ Time Frame: between baseline and week 48 ] [ Designated as safety issue: No ]
  The HIV Patient Symptoms Profile measures the tolerability of HIV treatment from the patient's perspective, using 14 concept scales in maximum 84 questions. The response options include a "no" or "yes" answer to "Did symptom occur?". If "yes", there is a problem scale which ranges from 1 = "I had this symptom and it was not a problem" to 5 = "I had this symptom and it was a severe problem". A neuropsychiatric tolerability score is composed as the sum of 21 items and ranges from 0 (best) to 105 (worse). A total Tolerability score (ie, the sum of all items) ranges from 0 (best) to 420 (worse)
• Neuropsychiatric Adverse Events by Week 48 [ Time Frame: from baseline to week 48 ] [ Designated as safety issue: No ]
  The percentage of patients with at least 1 treatment emergent Grade 1 -4 neurologic or psychiatric adverse event, judged by the investigator to be at least possibly related to the study drug.
• Mean Change From Baseline in CD4+ Cell Count [ Time Frame: at baseline and week 2, 6, 12, 24, 36 and 48 ] [ Designated as safety issue: No ]
  The mean change in CD4+ cell count from baseline was calculated with a last observation carried forward method; i.e. the last observed value was carried forward, irrespective of the reason for discontinuation.
• Resistance Determinations [ Time Frame: at baseline and all subsequent visits until week 48 in case if virologic failure ] [ Designated as safety issue: No ]
  The evolution of viral genotype and phenotype was assessed by the number of patients with resistance-associated mutations emerging at the endpoint. A mutation was considered emerging if it was present at endpoint and not present at baseline or any pre-baseline assessment. (NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; RAM = resistance-associated mutation, IAS-USA = International AIDS Society - USA)

• To evaluate and compare antiviral activity and immunologic responsesof ETR vs EFV as determined by plasma viral load, or measured by CD4+ T cell count respectively [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• To evaluate and compare the worst score during the treatment period in tolerability of ETR vs EFV according CNS and total Tolerability score, as calculated from patient report on the HIV PSP questionnaire [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
• To compare the percentage of patients with at least one treatment-emergent Grade 1-4 CNS or psychiatric adverse event, judged by the investigator to be at least possibly related to the study drug, in the ETR group versus the EFV group [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
• To evaluate and compare the incidence of treatment-limiting psychiatric and/or CNS adverse events of ETR versus EFV [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
• To evaluate and compare the safety and tolerability of ETR versus EFV over 48 weeks [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

The purpose of this study is to compare the neuropsychiatric adverse event profiles of etravirine 400mg once daily versus efavirenz 600mg once daily, in combination with 2 N(t)RTIs, in approximately 150 treatment-naÃ-ve HIV-1 infected patients. Safety, tolerability and efficacy of both treatment arms will be assessed throughout the study.

This is a phase IIb, randomised (study medication is assigned by chance), double-blind (neither the patient nor the study physician will know to which treatment group the patient is assigned) trial to assess the neuropsychiatric adverse event profile of etravirine (ETR) 400mg once daily versus efavirenz (EFV) 600mg once daily, each in combination with an investigator-selected background of 2 other anti-HIV drugs of the class nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs). The combination of N[t]RTIs to be chosen by the study physician can be abacavir (ABC)/lamivudine (3TC), zidovudine (AZT)/lamivudine (3TC) or tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Approximately 150 Human Immuno-deficiency Virus type 1 (HIV-1) infected patients, who have never received any antiretroviral (ARV) treatment will be randomly assigned (like tossing a coin) to either the etravirine treatment group or the control group (efavirenz). The study period includes a screening period of maximum 6 weeks, a 48 week treatment period, an additional 2-8 weeks treatment until unblinding (study physician (and patient) will receive information to which treatment group the patient is assigned), followed by a 4 weeks follow-up period. The main purpose of this study is to gather further data on how many, how often, and how severe the central nervous system and psychiatric (neuropsychiatric) events are between the two treatment groups. In addition, the study will look at overall safety, tolerability and antiviral effectiveness between the two treatment groups. During the trial, patients' health will be monitored by physical examination, checking of vital signs (blood pressure / pulse), and laboratory testing on blood and urine samples. Also blood samples will be drawn to measure the antiviral effectiveness (i.e., decrease of the plasma viral load to a level <50 HIV-1 RNA (ribonucleic acid) copies/mL), immunology assessments (to assess the body's immune system) and pharmacokinetic (to measure the drug level in blood) analysis of etravirine. Patients will be asked to complete the "HIV Patient Symptoms Profile" (HIV PSP) Questionnaire at each visit, which contains questions relating to the impact on patients' current health and well-being. The study hypothesis is that the proportion of patients with at least one neuropsychiatric adverse event related to the study drug, observed between start of treatment (Baseline; BSL) through Week 12, is significantly lower in the etravirine group than in the efavirenz group. Patients will be taking blinded medication twice a day, administered orally (by mouth). Only one of the blinded doses will contain an active ingredient. Etravirine 400mg (or dummy-pills) - 4 tablets - should be taken once a day, following a meal, preferably breakfast. Efavirenz 600mg (or dummy-pill) - 1 tablet - should be administered once daily on an empty stomach, preferably at bedtime.The intake of the investigator-selected N[t]RTIs should be taken as instructed by the investigator.

• HIV Infection
• HIV
• Acquired Immunodeficiency Syndrome

• Drug: etravirine (ETR, TMC125)
  400mg once daily (4x100mg tablet) + 2 NRTI + 1 EFV placebo tablet for 48 weeks
• Drug: efavirenz (EFV)
  600mg once daily (1x600mg tablet) + 2 NRTIs + 4 ETR placebo tablets for 48 weeks

• Experimental: etravirine
  etravirine (ETR TMC125) 400mg once daily (4x100mg tablet) + 2 NRTI + 1 EFV placebo tablet for 48 weeks
  Intervention: Drug: etravirine (ETR, TMC125)
• Active Comparator: efavirenz
  efavirenz (EFV) 600mg once daily (1x600mg tablet) + 2 NRTIs + 4 ETR placebo tablets for 48 weeks
  Intervention: Drug: efavirenz (EFV)

• Nelson M, Stellbrink HJ, Podzamczer D, Banhegyi D, Gazzard B, Hill A, van Delft Y, Vingerhoets J, Stark T, Marks S. A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. AIDS. 2011 Jan 28;25(3):335-40.
• Gazzard B, Duvivier C, Zagler C, Castagna A, Hill A, van Delft Y, Marks S. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS. 2011 Nov 28;25(18):2249-58. doi: 10.1097/QAD.0b013e32834c4c06.

Inclusion Criteria:

• Documented HIV-1 infection
• In the judgement of the investigator, it is appropriate to initiate ARV therapy based on the patients medical condition and taking into account applicable guidelines for the treatment of HIV-1 infection
• Patient has access to an investigator-selected ARV regimen post-study in accordance with applicable guidelines for the treatment of HIV-1 infection
• HIV-1 plasma viral load at screening >= 5000 HIV-1 RNA (copies/ml)
• Predicted phenotypic sensitivity to the currently approved NNRTIs and to the N(t)RTIs in their background regimen at screening

Exclusion Criteria:

• Any previous treatment with a therapeutic HIV vaccine or use of ARVs, including use of NVP for the prevention of vertical HIV transmission
• The presence of at least one of the mutations that are specific indicators of transmitted (or primary) drug resistance
• Known infection with HIV-2 or with HIV-1 group O
• Category C AIDS defining illness, except stable Kaposi's Sarcoma, wasting syndrome if not progressive
• Pneumocystis jiroveci/carinii Pneumonia (PCP) that is considered not cured
• Specific grade 3 or 4 laboratory abnormalities