TMC125-TiDP2-C238: An Exploratory Pharmacokinetics, Safety and Anti-HIV Activity Study of Etravirine (ETR) When Given With Boosted Atazanavir (ATV/Rtv) at Two Different Doses and 1 Nucleoside Reverse Transcriptase Inhibitor (NRTI) in Treatment Experienced HIV Patients

TMC125-TiDP2-C238: A Randomized, Exploratory, Open-label 48-week Trial to Investigate the Pharmacokinetics, Safety, Tolerability and Antiviral Activity of Etravirine (ETR) in Combination With Ritonavir-boosted Atazanavir (ATV/Rtv) and 1 NRTI in Treatment-experienced HIV-1 Infected Subjects

The purpose of this study is to determine the pharmacokinetics (how the body absorbs, distributes, metabolizes and eliminates a drug) (PK) of ETR when given with ATV/rtv and 1 NRTI in treatment experienced HIV-1 infected patients. In addition, safety, tolerability and anti-HIV effect of this regimen will also be studied. A total of 46 patients will be enrolled.

This is a randomized (study drug assigned by chance), exploratory, open-label (all involved people know the identity of the intervention) trial to evaluate the pharmacokinetics (PK), safety, tolerability and anti-HIV (anti Human Immunodeficiency Virus) activity of etravirine (ETR ) when given with atazanavir/ritonavir (ATV/rtv) and 1 nucleoside reverse transcriptase inhibitor (NRTI) in 46 treatment experienced HIV-1 infected patients. The trial will consist of : 4 weeks of Screening Period, 2 weeks Pre-Treatment Phase, 48-week Treatment Period, and a Final Visit followed by a 4-week Follow-up Period (only for patients not continuing treatment with ETR in another trial or program). Safety evaluations (AE reporting, labs, vital signs, etc.) will be monitored at each study visit. A PK substudy (included in the protocol, with optional participation) with tenofovir (TDF) added to the antiretroviral regimen for 7 days will be conducted in patients with > 24 weeks of treatment with suppressed HIV-1 viral load. In Pre-Treatment Phase, all patients will receive ATV/rtv 300/100 mg once daily to be taken following a meal each morning + 2 NRTIs (dose as specified in the labels) for 14 days. In Treatment Phase, patients will receive ETR 200 mg twice daily in addition to ATV/rtv (300/100 mg or 400/100 mg) once daily with meals + 1 investigator-selected NRTI for 48 weeks. In substudy TDF 300 mg once daily will be added to the treatment regimen x 7 days.

Inclusion Criteria:

- Documented HIV-1 infection

• Failing on a stable ART (anti retroviral therapy) with HIV-1 plasma viral load above 500 HIV-1 RNA copies/ml
• Presence of at least 1 documented NNRTI mutation
• Demonstrated sensitivity to ATV, ETR and at least one of the selected NRTIs based on the resistance test at screening
• General medical condition, in the investigator's opinion, does not interfere with the assessments and completion of the trial
• Substudy: patients who have been treated in C238 for more than 24 weeks and are currently suppressed (defined as patients with at least 2 most recent and consecutive viral loads less than 50 cp/mL) will be considered eligible for the substudy

Exclusion Criteria:

• Primary HIV-1 infection
• Previously documented HIV-2 infection
• Previously failed 2 or more HIV PI-containing regimens
• Previous diagnosis of hereditary hyperbilirubinemia (eg. Gilbert's syndrome, Crigler-Najjar syndrome).

Grade 3 or 4 toxicities (according to DAIDS grading)

• Acute and chronic viral hepatitis
• Receipt of an investigational drug or investigational vaccine within 30 days prior to the trial drug administration
• Pregnant or breastfeeding female