Purpose

This ‘pragmatic’ trial is a 2X2 open randomized study of patients in advanced HIV disease who have failed on conventional HAART (Highly Active Antiretroviral Therapy) regimens including all three classes of anti-HIV drugs. The first randomization will allocate patients to an intended 3-month antiretroviral drug-free period (ARDFP) or No ARDFP. The second randomization will allocate patients to Mega-ART (5+ drugs) or to Standard-ART (up to 4 drugs). The total study duration is 3.5 years with 2.5 years of intake and 1 year (minimum) of follow-up; median duration of patient follow-up is 2 years. The target sample size is 1700 patients and will provide 80% power to detect a 30% reduction in the hazard rate for the primary endpoint with mega-ART. Seventy-seven sites will be participating in the trial–30 VA, 25 UK and 22 Canada.

Purpose This ‘pragmatic’ trial is a 2X2 open randomized study of patients in advanced HIV disease who have failed on conventional HAART (Highly Active Antiretroviral Therapy) regimens including all three classes of anti-HIV drugs. The first randomization will allocate patients to an intended 3-month antiretroviral drug-free period (ARDFP) or No ARDFP. The second randomization will allocate patients to Mega-ART (5+ drugs) or to Standard-ART (up to 4 drugs). The total study duration is 3.5 years with 2.5 years of intake and 1 year (minimum) of follow-up; median duration of patient follow-up is 2 years. The target sample size is 1700 patients and will provide 80% power to detect a 30% reduction in the hazard rate for the primary endpoint with mega-ART. Seventy-seven sites will be participating in the trial–30 VA, 25 UK and 22 Canada. Condition: – AIDS- HIV Infections Study Type: InterventionalStudy Design: Treatment, Randomized, Open Label, Active Control, Factorial Assignment, Safety/Efficacy Study Official Title: CSP #512 – Options in Management with Anti-Retrovirals (OPTIMA), Management of Patients with HIV Infection for Whom First and Second-line Highly Active Anti-Retroviral Therapy has Failed Further Study Details: Primary Hypothesis:Compared to patients in Standard Antiretroviral Therapy (ART), patients in Mega-ART assuming full compliance, will experience a 30% reduction in the hazard of reaching a clinical endpoint (AIDS event or death). Secondary Hypotheses:Time to development of a new, non-HIV related serious adverse event, health related quality of life, the incidence of grade 3 or 4 clinical or laboratory adverse events and changes in virological and immunological markers (CD4 cell count, viral load, resistance profiles) will vary between the different treatment strategies. Primary Endpoint:1. Time to development of a new or recurrent AIDS event, or time to deathSecondary Endpoint:1. Time to development of a new non HIV-related serious adverse eventOther Outcomes:1. Quality of life2. Incidence of grade 3 or 4 clinical or laboratory adverse events3. Changes in CD4 counts, viral load, resistance patterns4. Process measures including hematologic profiles, electrolytes, renal, liver and pancreatic function and lipid levels.Interventions:Eligible patients will be randomized to one of four treatment strategy arms:a. No Antiretroviral Drug-Free Period (No ARDFP) and Standard-ARTb. No Antiretroviral Drug-Free Period (No ARDFP) and Mega-ARTc. Antiretroviral Drug-Free Period (ARDFP) and Standard-ARTd. Antiretroviral Drug-Free Period (ARDFP) and Mega-ARTNote: The ‘first’ randomization will be ARDFP vs No ARDFP. Patients randomized to No ARDFP will receive their ‘second’ randomization at the same time. However, patients randomized to an Antiretroviral Drug Free Period (ARDFP) will receive their ‘second’ randomized assignment (Standard or Mega-ART) at the end of the ARDFP. Study Abstract:This ‘pragmatic’ trial is a 2X2 open randomized study of patients in advanced HIV disease who have failed on conventional HAART (Highly Active Antiretroviral Therapy) regimens including all three classes of anti-HIV drugs. The first randomization will allocate patients to an intended 3-month antiretroviral drug-free period (ARDFP) or No ARDFP. The second randomization will allocate patients to Mega-ART (5+ drugs) or to Standard-ART (up to 4 drugs). The total study duration is 3.5 years with 2.5 years of intake and 1 year (minimum) of follow-up; median duration of patient follow-up is 2 years. The target sample size is 1700 patients and will provide 80% power to detect a 30% reduction in the hazard rate for the primary endpoint with mega-ART. Seventy-seven sites will be participating in the trial–30 VA, 25 UK and 22 Canada. This is the first trial of a Tri-National collaboration effort between the UK MRC, the Canadian CIHR and the VA CSP. The OPTIMA Trial was reviewed and approved by CSEC on October 12, 2000. The pre-kickoff meeting was held on March 21, 2001 in Washington, DC. The VA study kickoff meeting was held in Dallas, TX on May 16-18, 2001 and the Canadian kickoff was held in Toronto on May 29, 2001. The UK will have individual site initiation. As of October 16, 2002 there have been 136 patients enrolled in OPTIMA, at 60 sites in the three countries (110 in the VA, 19 in Canada and 7 in the UK). To date there are 60 sites actively participating in the study (25 in the VA, 15 in UK and 20 in Canada). Eligibility Ages Eligible for Study: 18 Years and above, Genders Eligible for Study: Both Criteria Inclusion Criteria:Ability to provide informed consent Age of 18 years or more Serologic or virologic diagnosis of HIV infection Failure of at least two different multi-drug regimens that include drugs of all 3 classes that the patient can tolerate or laboratory evidence of resistance to drugs in each of the 3 classes Had at least 3 months of current ART and are still on treatment Two most recent results (which can include screening) on current ART of: CD4 count less than or equal to 300 cells/mm3 or less than or equal to 15% , and a plasma viral load greater than or equal to 5,000 copies/ml (Roche Amplicor, v1.0), or greater than or equal to 2,500 copies/ml (by bDNA: Bayer v3.0/Chiron v3.0 or PCR:Roche Amplicor Monitor/COBAS v1.5) Exclusion Criteria:Pregnancy, breast-feeding or planned pregnancy Likelihood of poor protocol follow-up or if Mega-Art is not feasible (due to significant intolerance of many ARV drugs) Serious, uncontrolled major opportunistic infection (OI) within 14 days of screening Likelihood of early death due to non-HIV disease Expected Total Enrollment: 1700 (Source: Department of Veterans Affairs, Department of Veterans Affairs Cooperative Studies, Program Medical Research Council, Canadian Institutes of Health Research, March 2004)