Treatment Simplification by Darunavir/Ritonavir 800/100 mg Once a Day Versus a Triple Combination Therapy With Darunavir/Ritonavir (MONET)

• Virological Response [Intent To Treat (ITT) - TLOVR, < 50 Copies/ml, Week 48] [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  Virological response is defined as the number of patients in the ITT population with a plasma viral load < 50 HIV RNA copies/ml at Week 48. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure* (referred to as a Switch Equals Failure analysis). *Discontinuations and rechallenge with NRTIs are taken into account until start of Week 48 window
• Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, < 50 Copies/ml, Week 144] [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
  Virological response is defined as the number of patients in the PP population with a plasma viral load < 50 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure* (referred to as a Switch Equals Failure analysis). *Discontinuations and rechallenge with NRTIs are taken into account until Week 144
• Virological Response [Intent To Treat (ITT), TLOVR - All Switches Included, < 50 Copies/ml, Week 144] [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
  Virological response is defined as the number of patients in the ITT population with a plasma viral load < 50 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). All switches included means that all data even after any changes of treatment were kept. *Discontinuations and rechallenge with NRTIs are taken into account until start of Week 144 window.
• Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, <200 Copies/ml, Week 144] [ Time Frame: week 144 ] [ Designated as safety issue: No ]
  Virological response is defined as the number of patients in the PP population with a plasma viral load < 200 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure* (referred to as a Switch Equals Failure analysis). *Discontinuations and rechallenge with NRTIs are taken into account until Week 144
• Mean Change From Baseline in CD4+ Cell Count [ Time Frame: at week 4, 12, 24, 36, 48, 60, 72, 84, 96, 112, 128, 144 ] [ 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 each visit from baseline to week 144 ] [ Designated as safety issue: No ]
  Number of patients with resistance mutations at any time point when a patient had a viral load > 50 copies/mL after randomization.
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Total Score [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI is a validated health-related quality of life questionnaire. The questionnaire consist of 44 items and includes 5 functional scales (physical, social, emotional, functional and global well-being and cognitive function). Each item is assessing the impact of HIV on a scale from 0 (not at all) to 5 (very much).
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Cognitive Function Subscale [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI cognitive function subscale. Each item is assessing the impact of HIV on cognitive function on a scale from 0 (not at all) to 5 (very much).
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Emotional Well-Being Subscale [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI emotional well-being subscale. Each item is assessing the impact of HIV on emotional well-being on a scale from 0 (not at all) to 5 (very much).
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Functional and Global Well-Being Subscale [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI functional and global well-being subscale. Each item is assessing the impact of HIV on functional and global well-being on a scale from 0 (not at all) to 5 (very much).
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Physical Well-Being Subscale [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI physical well-being subscale. Each item is assessing the impact of HIV on physical well-being on a scale from 0 (not at all) to 5 (very much).
• Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Social Well-Being Subscale [ Time Frame: at baseline, week 48, 96 and 144 ] [ Designated as safety issue: No ]
  The FAHI social well-being subscale. Each item is assessing the impact of HIV on physical well-being on a scale from 0 (not at all) to 5 (very much).

The purpose of the study is to compare the efficacy, safety and tolerability of darunavir/ritonavir 800/100 mg once a day (O.D.) as a monotherapy versus a triple combination therapy containing 2 nucleosides and darunavir/ritonavir in 250 HIV-1 infected patients who have been on Highly Active Antiretroviral Therapy (HAART) and have plasma viral load below 50 copies/ml for at least 24 weeks.

This study is randomised (patients are assigned different treatments based on chance), controlled, open-label trial to compare the efficacy, safety and tolerability of darunavir/ritonavir (DRV/r) 800/100 mg once a day (O.D.) as a monotherapy versus a triple combination therapy containing 2 nucleosides and DRV/r in 250 HIV-1 infected patients. Patients will be considered eligible if they have not changed any antiretroviral drugs for at least 8 weeks prior to screening and have documented evidence of plasma viral load (or plasma HIV-1 RNA) < 50 copies/mL for at least 24 weeks prior to being screened. The trial will consist of a screening period up to 4 weeks, a 48-week treatment period, followed by a 4-week follow-up (FU) period. The primary objective is to demonstrate non-inferiority in efficacy of DRV/r versus the triple combination therapy containing DRV/r, with respect to confirmed virologic response, defined as plasma HIV-1 RNA < 50 copies/mL at 48 weeks.Patients will be assigned a study medication based on a 1:1 ratio to either switch to a triple combination therapy containing 2 nucleosides and DRV/r 800/100 mg O.D, or initiate monotherapy with DRV/r 800/100 mg O.D. Patients in the triple combination arm who are already on 2 nucleosides prior to randomisation may remain on these or switch them at baseline. Patients randomised to the monotherapy arm will discontinue Highly Active Antiretroviral Therapy (HAART) at baseline and commence DRV/r 800/100 mg O.D. A Data and Safety Monitoring Board (DSMB) has been commissioned for this study. The role of the DSMB is to review the progress of the trial and the accumulating data to detect evidence of early safety issues for the patients while the trial is ongoing. An interim analysis will be performed after 24 weeks of treatment. The results of the Week 24 analysis will be used to determine whether long-term follow-up to 72 and 96 weeks will be done. The protease inhibitor (PI) component of the regimen cannot be changed until the end of the treatment period and the nucleoside reverse transcriptase inhibitors (NRTIs) cannot be modified until the end of the treatment period with the following exception: single antiretroviral (ARV) substitutions will be allowed for tolerability/toxicity reasons, as long as this can be linked to an adverse event (AE) or an serious adverse event (SAE). After withdrawal of the patient from the trial, changes in the ARV regimen are allowed after the assessments of the withdrawal visit have been performed.

Temporary interruption of all ARVs will be allowed in the event of suspected toxicity, as long as the temporary interruption is associated with and can be linked to an AE or a SAE. For the control arm, the nucleoside analogues could be re-optimized at baseline or on study, and all approved ARVs allowed. However, PIs other than DRV/r are not allowed during the treatment period. Patients who cannot resume study medication will have to be withdrawn. A physical examination will be done at protocol-scheduled visits and vital signs will be monitored at each study visit. In addition, at each study visit, every patient will be asked about the occurrence of or change to AEs since they were last seen by the investigator. Laboratory samples for haematology and serum chemistry will be drawn and the results determined and transmitted to the investigator. Urinalysis will be performed. Pregnancy test will be done at each visit for female participants of child-bearing potential. The primary endpoint will be the proportion with virologic response, defined as a confirmed plasma HIV-1 RNA < 50 copies/mL at Week 48.The study hypothesis is that DRV/r monotherapy will be as effective as a triple combination regimen and will be well tolerated in this early pre-treated HIV-1 patients. Two 400mg tablets of darunavir once daily orally within 30 minutes after completion of a meal for 48 weeks.

• HIV Infections
• AIDS Virus
• Human Immunodeficiency Virus
• Acquired Immunodeficiency Syndrome Virus

• Drug: darunavir (DRV, TMC114)
  800 mg qd (2 x 400 mg tablet) + 2 NRTI for 144 weeks
• Drug: darunavir (DRV, TMC114)
  800 mg qd (2 x 400 mg tablet) monotherapy for 144 weeks

• Experimental: darunavir monotherapy
  darunavir (DRV, TMC114) 800 mg qd (2 x 400 mg tablet) monotherapy for 144 weeks
  Intervention: Drug: darunavir (DRV, TMC114)
• Experimental: darunavir + 2 NRTI
  darunavir (DRV, TMC114) 800 mg qd (2 x 400 mg tablet) + 2 NRTI for 144 weeks
  Intervention: Drug: darunavir (DRV, TMC114)

Inclusion Criteria:

• Patients with documented HIV-1 infection
• Patients currently receiving HAART for at least 24 weeks
• Plasma viral load < 50 copies/mL for at least 24 weeks prior to screening (two results must be documented)
• Patients taking the same antiretroviral combination for at least 8 weeks before screening
• Patients and physician's preference to change the current HAART regimen for reasons of simplification and/or toxicity
• CD4 > 100/mm3 at the start of HAART and > 200/mm3 at screening.

Exclusion Criteria:

• No history of virological failure defined as two consecutive plasma HIV-1 RNA > 500 copies/mL while on previous or current antiretroviral therapy
• No history of any primary PI mutations as defined by the IAS-USA guidelines 2006
• No patients co-infected with hepatitis B
• No pregnant or breastfeeding women
• No active clinically significant disease or life threatening disease or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the patient's safety or outcome of the study.