Safety and Efficacy of Reduced Dose Efavirenz (EFV) With Standard Dose EFV Plus Two Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) in Antiretroviral-naïve HIV-infected Individuals. (encore1)

• Virologic endpoints: proportion of patients with plasma HIV RNA <400 copies/mL and <50 copies/mL, and time to virological failure (HIV RNA ≥200 copies/ml) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Immunologic endpoints: mean change from baseline in CD4+ T cell count/µL [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Clinical endpoints: rate of opportunistic disease or death, and rates of serious non-AIDS-defining illness and non-AIDS-related mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Metabolic endpoints: mean/median change from baseline in fasted lipids (TC, LDL-c, HDL-c and TG), mean/median change from baseline in fasted glucose, and rates of initiation or changes in existing lipid-lowering therapies [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Adherence: median scores of self-reported adherence to randomised study medications [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Mean/median change from baseline in selected serum biochemical parameters [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Rates, types and severity of adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Steady state EFV concentrations [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Steady state EFV concentrations measured by plasma and dried blood spot samples

• Virologic endpoints: proportion of patients at 96 weeks with plasma HIV RNA <400 copies/mL and <50 copies/mL, and time to virological failure (HIV RNA ≥200 copies/ml) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Immunologic endpoints: mean change from baseline to week 96 in CD4+ T cell count/µL [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Clinical endpoints: rate of opportunistic disease or death, and rates of serious non-AIDS-defining illness and non-AIDS-related mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Metabolic endpoints: mean/median change from baseline to week 96 in fasted lipids (TC, LDL-c, HDL-c and TG), mean/median change from baseline to week 96 changes in fasted glucose, and rates of initiation or changes in existing lipid-lowering therapies [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Adherence: median scores of self-reported adherence to randomised study medications [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Clinical data suggests that the standard dose of the anti-HIV medication, efavirenz (EFV), could be reduced without compromising its effectiveness. Lower drug doses could have fewer side effects and would make EFV more affordable. The purpose of this study is to compare the safety and effectiveness, over 96 weeks, of standard (600mg) versus reduced dose (400mg) EFV in controlling HIV as part of initial combination antiretroviral therapy.

In this international, multicenter trial, 630 HIV infected patients who have not received any previous treatment for their HIV-infection will be enrolled. Participants will be randomized equally (1:1) to receive truvada (tenofovir and emtricitabine) with either the standard or reduced dose of EFV. Neither the study doctor nor the participant will know which treatment the participant is receiving. Physical examinations, laboratory analyses and questionnaires will be performed at the 11 study visits at screening, baseline (Week 0), Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96. The primary aim of this study is to compare between treatment groups the proportion of patients with undetectable HIV viral load (HIV RNA < 200 copies/mL) after 48 weeks. Information on immune function, drug adherence, resistance to antiretrovirals, quality of life, mental state and HIV-related conditions will also be collected. Blood samples will be collected for future testing. Interim analyses will be performed when the first 125 participants in each treatment group reach week 24 and when all participants reach week 24. These interim analyses will provide an early check that the reduced dose of EFV suppresses HIV infection as effectively as the standard dose of EFV. A follow-up analysis will be performed when all participants reach week 96.

• Drug: Efavirenz
  3 x EFV 200mg tablets once daily
  Other Name: Matrix EFV 200mg (Efamat 200) tablets
• Drug: Efavirenz
  2 x EFV 200mg tablets plus 1x matched EFV placebo tablet once daily
  Other Names:

  • Matrix EFV 200mg (Efamat 200) tablets
  • Matrix EFV 200mg (Efamat 200) matched placebo tablets.

• Active Comparator: 600mg Efavirenz
  Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd)
  Intervention: Drug: Efavirenz
• Experimental: 400mg Efavirenz
  Eligible patients will be centrally randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd).
  Intervention: Drug: Efavirenz

Inclusion Criteria:

• HIV-1 positive by licensed diagnostic test
• aged >16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)
• 50 < CD4 <500 cells/µL
• No prior AIDS-defining illness, using the CDC 1993 case definition (except pulmonary tuberculosis)
• HIV RNA ≥1000 copies/mL
• no prior exposure to ART (including short course ARVs for preventing MTCT)
• calculated creatinine clearance (CLCr) more than or equal to 50 mL/min (Cockcroft-Gault formula)
• provision of written informed consent.

Exclusion Criteria:

• the following laboratory values:

  • absolute neutrophil count (ANC) <500 cells/μL
  • hemoglobin <7.0 g/dL
  • platelet count <50,000 cells/μL
  • AST and/or ALT >5 x ULN
• pregnant women or nursing mothers
• active opportunistic or malignant disease not under adequate control
• use of immunomodulators within 30 days prior to screening
• use of any prohibited medications
• current alcohol or illicit substance use that might adversely affect study participation