Efficacy and Safety Study of Darunavir for the Treatment of HIV/AIDS
Condition: HIV/AIDS
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: Darunavir; ART with 2 NRTIs plus LPV/r (or ATV/r)
Intervention description: Darunavir (PREZISTA) is a film coated, oval shaped, light orange 19.1mm tablet, debossed with 400 mg on one side and TMC on the other side.; Patients on second line antiretroviral therapy take 2 NRTIs and either protease inhibitor lopinavir/ritonavir or atazanavir/ritonavir.
Intervention MeSH terms: Ritonavir; Lopinavir; Atazanavir Sulfate; Darunavir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 120.0
Sex: All
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Efficacy; Safety; Darunavir; HIV-1 RNA level; Cameroon

Summary:

      The aim of this pilot study is to assess the feasibility, efficacy and safety of
      Darunavir/ritonavir 800/100 mg once daily (DRV/r) monotherapy as a switch-maintenance
      strategy for patients receiving second-line ART at Yaoundé Central Hospital in Cameroon.
      HIV-infected adults receiving second-line antiretroviral therapy (ART) for ≥3 months with 2
      nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir
      (LPV/r) or atazanavir/ritonavir (ATV/r) will undergo plasma HIV-1 RNA ("viral") load testing.
      Those with a viral load below 50 copies/ml (<50 cps/ml) will undergo a repeat test ideally
      4-6 weeks later (allowed up to 12 weeks); if the viral load is confirmed as <50 cps/ml the
      patient will be invited to join the randomised phase of the study. Patients (n=150) will be
      randomised 1:2 to either continue the current triple ART regimen (n=50) or switch to DRV/r
      monotherapy (n=100). The primary end-point will be viral load suppression <400 cps/ml at week
      24; secondary end-points will be viral load suppression <50 cps/ml at week 12 and week 24,
      safety, tolerability, and emergence of protease inhibitor (PI) drug-resistance. Patients will
      continue observational follow-up depending on the treatment arm they are randomized to. After
      week 48, patients will return to local standard of care. Pharmacokinetics (PK) and
      pharmacogenomics sub-study to correlate plasma concentrations of DRV to outcomes, HIV-1 drug
      resistance testing sub study to detect mutants archived at the time of first-line ART failure
      and measuring HIV DNA load will be performed, as well as a cost-effectiveness analysis will
      test the hypothesis that savings can be achieved by switching to DRV/r monotherapy without
      affecting quality of care. The primary virological objective is to evaluate efficacy in terms
      of the percentage of subjects who have plasma HIV-1 RNA levels <400 cps/ml after 24 weeks of
      follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing
      2 NRTIs + LPV/r (or ATV/r) (FDA Snapshot method).

      Study hypothesis:

      we propose that maintenance therapy with DRV/r monotherapy is a feasible, effective and safe
      treatment option for patients receiving second-line ART in Yaoundé.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects with documented HIV-1 infection.

          2. Male or female aged > 21 years old.

          3. Subjects receiving ART with 2 NRTIs + LPV/r (or ATV/r) for at least 3 months at the
             time of Screening 1.

          4. Nadir T lymphocyte cluster of differentiation 4 (CD4) >100 cells/mm3

          5. Plasma HIV-1 RNA <50 copies/ml at Screening 1 confirmed ideally 4-6 weeks later at
             Screening 2 (two results must be documented; a first result obtained up to 12 weeks
             earlier will be accepted).

          6. Subjects can comply with the protocol requirements. In particular, subjects should be
             willing to be followed up at least until week 24 (discontinuation prior to week 24)
             and for the DRV/r arm up to week 48 (discontinuation after week 24) even if they
             discontinue randomized treatment.

          7. Subjects who have voluntarily signed and dated the consent form.

        Exclusion Criteria:

          1. Clinical or laboratory evidence of significantly decreased hepatic function or
             decompensation, irrespective of liver enzyme levels (liver insufficiency).

          2. Co-infection with hepatitis B (HBsAg positive).

          3. Grade 3 or 4 laboratory abnormality as defined by AIDS, including haemoglobin ≤8mg/dL;
             platelets ≤50 000/mm3; estimated creatinine clearance ≤60ml/ minute, aspartate
             aminotransferase; alanine aminotransferase and alkaline phosphatase >3 times the upper
             limit of normal; and total bilirubin >2.5 times the upper limit of normal; with the
             following exceptions unless clinical assessment foresees an immediate health risk to
             the subject:

               -  Pre-existing diabetes or asymptomatic glucose grade 3 or 4 elevations.

               -  Asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.

          4. Presence of any currently active AIDS defining illness (Category C conditions
             according to the Centers for Disease Control Classification System for HIV Infection
             1993) with the following exceptions:

               -  Stable cutaneous Kaposi's Sarcoma (i.e., no internal organ involvement other than
                  oral lesions) that is unlikely to require any form of systemic therapy during the
                  study.

               -  Wasting syndrome due to HIV infection. Note: An AIDS defining illness that is not
                  clinically stabilized for at least 30 days will be considered as currently
                  active.

          5. Pregnant or breastfeeding women.

          6. Active substance abuse, including alcohol or recreational drugs.

          7. Any clinically significant disease (e.g., tuberculosis, cardiac dysfunction,
             pancreatitis, acute viral infections) or life threatening disease in the previous 14
             days, or findings during screening of medical history or physical examination that, in
             the investigator's opinion, would compromise the subject's safety or outcome of the
             study.

          8. Any medical or psychiatric condition which, in the opinion of the investigator, could
             compromise the subject's safety or adherence to the trial protocol.

          9. Previously demonstrated clinically allergy or hypersensitivity to any of the
             excipients of the investigational medication (DRV).

             Note: DRV is a sulfonamide. Subjects who have previously experienced a sulfonamide
             allergy will be allowed to enter the trial. To date, no potential for cross
             sensitivity between drugs in the sulfonamide class and DRV has been identified in
             subjects participating in phase II trials.

         10. Participation in any other clinical trials that involve administration of
             antiretrovirals or other drugs within the last 4 weeks and during the participation in
             this trial.