A Multicentre Trial of Second-line Antiretroviral Treatment Strategies in African Adults Using Atazanavir or Lopinavir/Ritonavir (ALISA)

• Virological response [ Time Frame: 12 and 24 weeks ] [ Designated as safety issue: No ]
  Proportion of patients with plasma HIV RNA < 400 copies/mL
• Viral resistance [ Time Frame: 12, 24 and 48 weeks ] [ Designated as safety issue: No ]
  Incidence of resistance mutations after treatment failure (HIV RNA < 1000 copies/mL)
• Clinical course of HIV infection [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: Yes ]
  Mortality, occurence of clinical events stage 3 or 4 (WHO classification), immune reconstitution sundrome, non-AIDS clinical events including bacterial infections
• Tolerance assessment [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: Yes ]
  Proportion of adverse events related to antiretroviral treatment, proportion of treatement discontinuations due to antiretroviral side effect, variation of biological parameters and metabolic markers between second line antiretroviral initiation and 24/48 weeks.
• Adherence assessment [ Time Frame: At each protocol visit : week 2, 4, 12, 24, 36 and 48 ] [ Designated as safety issue: No ]
  Measurement of pills consumption at each visit, face-to-face questionnaire with the pharmacist
• Hepatitis B evaluation [ Time Frame: At entry ] [ Designated as safety issue: No ]
  Prevalence of HBs AG, HBe Ag, HBV viremia, and HBV asociated drug resistance mutations at baseline
• Immunologic response [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
  Variation of circulating total and CD4+ lymphocyte count between second line treatment initiation and 24 weeks/48 weeks

In the well recognized context of HIV infection chronicity, it is now crucial to identify and evaluate effective, well tolerated and affordable second line regimen in resources limited countries where patients often change treatment after a long period of viral replication while on first line regimen.

This multicentre international, randomized, non-blinded phase III trial aim to demonstrate the non-inferiority of a generic lamivudine-tenofovir-atazanavir/ritonavir regimen (daily intake) as compared to a standard emtricitabine-tenofovir-lopinavir/ritonavir (twice daily intake)regimen for second line HIV-1 treatment. by stratifying on the viral load level (between 1000 and 5000 copies/mL versus > 5000 copies/mL) at inclusion, this trial will also allow to evaluate the optimum moment for instituting the second-line treatment.

• Drug: Lopinavir
  Evaluation of second line antiretroviral regimen including boosted lopinavir
• Drug: Atazanavir
  Evaluation of second line antiretroviral regimen including boosted atazanavir

• Active Comparator: Arm A : Lopinavir

  Emtricitabine/tenofovir :

  • TDF300mg.FTC200mg (Fixed Dose Combination)
  • 1 tablet per day

  Lopinavir/ritonavir :

  • LPV200mg/RTV50mg
  • 2 tablets twice a day
  Intervention: Drug: Lopinavir
• Experimental: Arm B : Atazanavir

  Lamivudine/tenofovir :

  • 3TC300mg/TDF300mg (Fixed Dose Combination)
  • 1 tablet per day

  Atazanavir/ritonavir :

  • ATV300mg/RTV100mg
  • 2 tablets once a day
  Intervention: Drug: Atazanavir

Inclusion Criteria:

• age 18 and above
• out patient
• documented HIV-1 infection

• first line treatment failure:

  • after first-line antiretroviral treatment with a combination including a non-nucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors
  • two measurements of plasma HIV RNA levels > 1000 copies/mL after at least 6 months of uninterrupted treatment or without any major modification
• satisfactory compliance (>80%) to 1st line antiretroviral treatment
• signed informed consent
• agreement for contraception for women of childbearing age

Exclusion Criteria:

• HIV-2 infection or HIV-1/HIV-2 coinfection
• uncontrolled, ongoing opportunistic infection or of any severe or progressive disease including active TB
• first line antiretroviral treatment with a protease inhibitor or tenofovir
• ongoing treatment with rifampicin
• severe hepatic insufficiency (PT < 50%)
• ALT < 3 times the upper limit of normal
• creatinine clearance calculated by Cockcroft's formula < 50 mL/min
• Hb <=8 g/dL; platelets < 50,000 cells/mm3; neutrophils < 500 cells/mm3
• pregnancy and lactation

• European and Developing Countries Clinical Trials Partnership (EDCTP)
• Ludwig-Maximilians - University of Munich
• Institute of Tropical Medicine, Belgium
• Institut de Recherche pour le Developpement, France
• Swiss National Science Foundation
• University of Limpopo
• NIMR-Mbeya Medical Research Program (MMRP)/ Mbeya Referral Hospital, Tanzania