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

A Randomised, Open-label, 96-week Study Comparing the Safety and Efficacy of Three Different Combination Antiretroviral Regimens as Initial Therapy for HIV Infection.

In treatment naïve HIV infected subjects, combination antiretroviral therapy including efavirenz combined with tenofovir and emtricitabine will offer non-inferior antiretroviral efficacy over 48 weeks, compared to either atazanavir boosted with ritonavir combined with tenofovir and emtricitabine or tenofovir and emtricitabine combined with zidovudine and abacavir, as assessed by change from baseline plasma HIV-1 RNA viral load.

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,

1. Percentage of patients < 50 copies HIV RNA/mL (and < 400 copies/mL) at week 48 and week 96 between treatment arms.
2. Time to confirmed (first of two consecutive) plasma HIV-1 RNA < 50 copies/mL (and < 400 copies/mL) between treatment arms.
3. 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).
4. Mean change from baseline of absolute CD4+ T cell count at weeks 48 and 96 between treatment arms.
5. Time to change in randomly assigned therapy (all reasons individually and on aggregate) between treatment arms.
6. Time to first virologic failure (defined as #3 above) or cessation of randomly assigned antiretroviral therapy.
7. Mean change from baseline Lipodystrophy Case Definition score at weeks 48 and 96 between treatment arms.
8. Mean change from baseline in peripheral and central adipose tissue, as measured by CT and DEXA at weeks 48 and 96 between treatment arms.
9. Mean change from baseline in fasting lipid and glycemic parameters at weeks 48 and 96 between treatment arms.
10. Comparison of total number of patients with any serious adverse events (SAEs), and the cumulative incidence of SAEs, between treatment arms.
11. 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.
12. Patterns of genotypic HIV resistance associated with virological treatment failure across treatment arms.
13. Describe aspects of immune reconstitution disease.
14. Adherence to therapy and associations with virologic outcomes between treatment arms.
15. 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).