ALTAIR - Alternative Antiretroviral Strategies : a Comparison of Three Initial Regimens

The primary objective of this study is to compare the virological efficacy, as measured by the time-weighted mean change from baseline plasma HIV-RNA, and safety, of three strategic regimens of initial antiretroviral therapy (ART) containing a fixed dose formulation of tenofovir and emtricitabine, with either efavirenz or ritonavir boosted atazanavir or zidovudine plus abacavir. (Primary comparisons are regimen I versus II and I versus III as described below).

I. tenofovir (TDF) + emtricitabine (FTC) + efavirenz (EFV) II. tenofovir (TDF) + emtricitabine (FTC) + ritonavir/atazanavir (r/ATV) III. tenofovir (TDF) + emtricitabine (FTC) + zidovudine (ZDV) + abacavir (ABC)

Secondary objectives of this study will be to undertake a range of analyses including but not limited to the following,

• Percentage of patients < 50 copies HIV RNA/mL (and < 400 copies/mL) at week 48 and week 96 between treatment arms.
• Time to confirmed (first of two consecutive) plasma HIV-1 RNA < 50 copies/mL (and < 400 copies/mL) between treatment arms.
• Time to virologic failure defined as confirmed plasma HIV-1 RNA > 50 copies/mL (and 400 copies/mL) after confirmed < 50 copies/mL (where time = 0 if patient never achieves plasma virus load < 50 or <400 copies/mL).
• Mean change from baseline of absolute CD4+ T cell count at weeks 48 and 96 between treatment arms.
• Time to change in randomly assigned therapy (all reasons individually and on aggregate) between treatment arms.
• Time to first virologic failure (defined as #3 above) or cessation of randomly assigned antiretroviral therapy.
• Mean change from baseline Lipodystrophy Case Definition score at weeks 48 and 96 between treatment arms.
• Mean change from baseline in peripheral and central adipose tissue, as measured by CT and DEXA at weeks 48 and 96 between treatment arms.
• Mean change from baseline in fasting lipid and glycemic parameters at weeks 48 and 96 between treatment arms.
• Comparison of total number of patients with any serious adverse events (SAEs), and the cumulative incidence of SAEs, between treatment arms.
• Comparison of total number of patients with any adverse events (AEs), and the cumulative incidence of AEs, associated with cessation of randomly assigned therapy between treatment arms.
• Patterns of genotypic HIV resistance associated with virological treatment failure across treatment arms.
• Describe aspects of immune reconstitution disease.
• Adherence to therapy and associations with virologic outcomes between treatment arms.
• Comparison of quality of life between treatment arms.

Following the result of the scheduled week 48 data analysis, the protocol steering committee amended the study protocol as follows:

• Patients on Arms I and II will remain on the current study drugs
• Patients on Arm III may be switched at the physician's discretion to either Arm I or II
• There will be a protocol amendment to include one extra follow up visit at week 144 for all patients, regardless of treatment arm or current treatment
• All patients are to be encouraged to stay on the study up to week 144, to maximize follow up on study.

Inclusion criteria

• HIV-1 positive by licensed diagnostic test with presumed duration of infection > 6 months from date of randomisation.
• Aged > 16 years of age (or minimum age as determined by local regulations or as legal requirements dictate).
• Antiretroviral treatment naïve.
• Qualifying plasma HIV RNA > 2,000 copies/mL and a CD4+ T cell count of ≥ 50 cells/µL.
• No evidence of harbouring a drug resistant HIV (based upon genotypic drug testing).
• Calculated creatinine clearance (CLCr) greater than or equal to 70 mL/min (Cockcroft-Gault formula).
• Able to provide written informed consent.

Exclusion criteria

• The following laboratory variables,

• absolute neutrophil count (ANC) < 750 cells/µL
• haemoglobin < 8.0 g/dL
• platelet count < 50,000 cells/µL
• serum AST, ALT > 5 x upper limit of normal (ULN)
• serum bilirubin > 1.5 x ULN
• Pregnant or nursing mothers.
• Current use of human growth hormone, testosterone or other anabolic steroid.
• Current use of any prohibited medications as described in product specific information.
• Acute therapy for serious infection or other serious medical illness (in the judgement of the site Principal Investigator) requiring systemic treatment and/or hospitalisation.
• Patients with current alcohol or illicit substance use that in the opinion of the site Principal Investigator would conflict with any aspect of the conduct of the trial.
• Patients unlikely to be able to remain in follow-up for the protocol-defined period.
• Patients with known renal insufficiency.
• Patients with obstructive liver disease.
• Patients with intractable diarrhoea (six loose stools/day for at least seven consecutive days).
• History of acute or chronic pancreatitis.
• Presence of cardiomyopathy (due to any cause) or any significant cardiovascular disease, such as unstable ischemic heart disease.
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated).