Once Daily 3TC, Efavirenz and ddI for HIV Infection

A Randomised, Multi-Centre, Open-Label Study in Well-Controlled Treatment-Experienced HIV-Infected Patients to Assess Compliance With a Once-Daily Regimen of Lamivudine, Efavirenz and Didanosine Versus Continuation of Current Anti-Retroviral Regimen Delivered at Least Twice Daily

Poor compliance is thought to be a major cause of treatment failure. The TEddI study is a randomised, multi-centre, open-label study in well-controlled treatment-experienced HIV-infected patients to assess compliance with a once-daily regimen of antiretroviral therapy versus continuation of current anti-retroviral regimen delivered at least twice daily.

Rationale: 'TEddI' will enable a once-daily treatment strategy to be studied and provide information on effectiveness, patient adherence and quality of life and the tolerability of such regimens.

Hypothesis: The study hypothesis is that an antiretroviral regimen comprising of three agents taken once daily will have higher levels of adherence than a regimen requiring more frequent dosing.

Primary objective: To determine over 24 weeks the levels of adherence in two groups of HIV-infected subjects randomised to receive either a once daily minimum 3-drug regimen or to continue a minimum 3-drug regimen requiring more frequent dosing.

Secondary objectives: The secondary objectives of the study will include:

• To estimate the proportion of patients with treatment failure where treatment failure is defined as:
• HIV-1 RNA viral load of >400 copies/ml on two consecutive occasions more than one month apart, OR
• Discontinuation of treatment for any reason (where subsequent therapy does not comply with the study regimen change guidelines outlined in section 3.3.3)
• Proportion of patients with plasma HIV-RNA less than 50 copies/ml (using an ultrasensitive assay) at 24 and 48 weeks
• Change from baseline in CD4 cell count at 24 and 48 weeks
• Changes from baseline in subjects' quality of life at 24 and 48 weeks
• Changes from baseline based on DASS 21 scores at 24 and 48 weeks
• Incidence and severity of adverse events and abnormal laboratory values (grade 3 & 4) at 24 and 48 weeks
• Proportion of patients remaining on assigned treatment Study Design This is a randomised, open-label, multi-centre, prospective, 48-week study comparing a 3 (or more) drug once-daily antiretroviral regimen with any 3 (or more) drug regimen in which at least 1 drug must be taken at least twice daily.

One hundred and twenty (120) subjects will be recruited and randomised in a 1:1 ratio to one of two open-label treatment regimens and will continue to receive randomised treatment until week 24:

Arm 1: (Once daily arm) commence treatment with a once-a-day combination of licensed antiviral medications (such as EFV/ddI/3TC, EFV/3TC/TDF or ATV/3TC/TDF).

Arm 2: (Continuation arm) continue current ART (minimum 3-drugs) dosed twice daily or more frequently

Following week 24, patients will have the option to continue randomised treatment for a further 24 weeks or switch to the once daily treatment arm. In all cases, patients will be followed up for 48 weeks from the baseline visit.

Inclusion Criteria:

• aged 18 years or more with laboratory evidence of HIV-1 infection
• ability to understand and provide written informed consent to participate in the study
• stable on current ART regimen for at least 3 months prior to screening.
• plasma HIV-RNA less than 400 copies/ml at the screening visit.
• women of child bearing potential must have a negative serum or urine β-HCG pregnancy test within 14 days prior to week -4 (assessment of study eligibility)

Exclusion Criteria:

• virological failure of a proposed Once daily arm medication
• a serious medical condition which may compromise the subject's safety, including an active AIDS-defining condition within the previous 6 months
• known toxicities to any of the proposed Once daily arm medications
• laboratory abnormalities at screening:
• serum creatinine greater than twice the upper limit of normal (2 x upper limit of normal (ULN))
• AST, ALT or alkaline phosphatase greater than 5 times the ULN
• lactate greater than 2.5 x ULN
• haemoglobin less than 9.5 g/dL
• women who are pregnant or breast-feeding or who, if of child-bearing potential, are not willing to use adequate contraception (including barrier contraception)
• patients who in the investigator's opinion are unlikely to complete the study