A Prospective, Open-label Trial of Two ABC/3TC Based Regimens in Late Presenter naïve Patients (CD4 <200 Cells/µL)

A Prospective, Open-label Trial of Two Abacavir/Lamivudine Based Regimen (ABC/3TC + Darunavir/Ritonavir or ABC/3TC + Raltegravir) in Late Presenter naïve Patients (With CD4 Count <200 Cells/µL - Advanced HIV Disease)

1. PROTOCOL SUMMARY This is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

1.1 Clinical Objectives: Primary Objective: To compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

Secondary Objective: a) To compare immunological response at 48 weeks; b) To determine the safety and tolerability of the 2 regimens.

1.2 Study population: 350 in/out patients 1.3 Outcome Primary Endpoint

• Proportion of patients with HIV RNA<50 copies/mL after 48 weeks Secondary Endpoints(s)
• Change in CD4+ cell count from baseline through week 48
• Time to virological rebound 1.4 Study design: Multicentre, parallel group, randomised, open label, non-inferiority study 1.5 Treatment regimens: Arm A: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) Arm B: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day.

All drugs have been approved for the treatment of HIV infection. The study population will consist of 350 HIV-positive, HLA B5701-negative patients. At baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. Randomization will be stratified on the basis of the screening CD4+ cell count (≤100 vs ≥100 cells/µL), to ensure balance across treatments groups 1.7 Criteria for Safety: Adverse events and laboratory assessments. 1.8 Statistical analysis: As this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. Non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. In case non-inferiority will be met, analyses for superiority will be performed.

1. PROTOCOL SUMMARY This is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

1.1 Clinical Objectives: Primary Objective: To compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

Secondary Objective:

1. To compare immunological response at 48 weeks;

2. To determine the safety and tolerability of the 2 regimens. 1.2 Study population: 350 inpatients or outpatients will be randomized 1.3 Outcome Primary Endpoint

   • Proportion of patients with undetectable viremia (HIV RNA<50 copies/mL) after 48 weeks Secondary Endpoints(s)
   • Change in CD4+ cell count from baseline through week 48
   • Time to virological rebound Safety endpoints
   • Incidence of adverse events (AEs)
   • Incidence of serious adverse events (SAEs)
   • Discontinuations due to adverse events
   • Incidence of grade 3 or 4 laboratory abnormalities. 1.4 Study design Multicentre, parallel group, randomised, open label, non-inferiority study 1.5 Planned sample size: The planned sample size for this trial is 350 patients 1.6 Treatment regimens: Arm A: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) Arm B: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day.

All drugs have been approved for the treatment of HIV infection. Administration: oral The study population will consist of 350 HIV-positive, HLA B5701-negative patients. At baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. Randomization will be stratified on the basis of the screening CD4+ cell count (≤100 vs ≥100 cells/µL), to ensure balance across treatments groups 1.7 Criteria for Safety: Adverse events and laboratory assessments. 1.8 Statistical analysis: As this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. Non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. In case non-inferiority will be met, analyses for superiority will be performed.

Inclusion Criteria:

1. Males or females (inpatients or outpatients) aged 18-64 years who are HIV-1 antibody seropositive, with a CD4 count <200 cells/uL.
2. All patients should be antiretroviral-naive
3. All patients should be HLA B57 or HLA B5701 negative
4. Patients must have an HIV RNA level <500,000 copies/mL
5. Patients with an active opportunistic infection could be enrolled as long as this was diagnosed more than 2 weeks prior to screening.
6. Patients must meet the following laboratory criteria. Neutrophil count > 1,000 cells/mm3 Haemoglobin > 9.0 grams/dl (men and women) Platelet count ≥ 75,000 cells/mm3 Alkaline phosphatase < 3.0 the upper limit of normal ALT and AST < 3.9 times the upper limit of normal Total bilirubin < 1.5 times the upper limit of normal.
7. Female patients of childbearing potential must be willing to use a reliable form of contraception, which will include a medically approved form of barrier contraception.
8. Patients must be able to provide written consent to comply with study requirements.

Exclusion Criteria:

1. Patients with genotypic mutations for any of the study drugs.
2. Patients with an opportunistic infection diagnosed in the 2 weeks prior to screening.
3. Female patients who are pregnant or breastfeeding.
4. Patients who are receiving any investigational drug or anti-neoplastic radiotherapy/chemotherapy other than local skin radiotherapy within 12 weeks before randomization.
5. Patients with a current history of intravenous drug abuse, alcohol or substance abuse.