Safety of Saquinavir and High Doses of Lopinavir/Ritonavir in Children With HIV
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to determine the effect of increased doses of
      lopinavir/ritonavir (LPV/r) and saquinavir (SQV) in HIV infected children who are failing
      their current antiretroviral regimen
    

Detailed description: 
      Since current drugs cannot cure HIV infection, lifelong therapy is required. Development of
      drug resistance is common, with 30% to 80% of patients with initial viral load decreases
      following a potent anti-HIV regimen experiencing regimen failure within the first year of
      therapy. Dose intensification (increasing dosing of treatment medications) has been used
      successfully in pediatric oncology. Dose intensification in HIV infected patients may
      overcome resistance and, as similarly observed in cancer, may result in a greater rate of
      viral inhibition, maximizing the degree and durability of viral suppression. This study will
      evaluate dose intensification in HIV infected children and adolescents who are failing their
      current antiretroviral regimen and have significant genotypic and phenotypic resistance.

      Participants in this 3-step study will have previously undergone genotypic resistance testing
      as part of their regular clinical care. Participants will have phenotypic resistance testing
      done at screening or within 6 months prior to study entry. Participants in this study will
      have either a genotypic profile with at least 4 of the required protease mutations or
      phenotypic resistance to LPV that is at least fivefold greater than wild type while on a
      failing regimen within 6 months of study screening.

      In Step 1, Group 1 participants will be randomly assigned to either a drug regimen without a
      nonnucleoside reverse transcriptase inhibitor (NNRTI) or a drug regimen with an NNRTI for
      Group 2 participants. Participants and their doctors will work with study investigators to
      select the best treatment regimen possible. All participants in the study will receive LPV/r
      as part of their drug regimens. Participants in Group 1 will take a higher dose of LPV/r than
      participants in Group 2 because NNRTIs lower LPV/r levels in the blood.

      At Week 2, participants will undergo a 12-hour pharmacokinetic (PK) test to evaluate the drug
      levels in their blood. If LPV/r levels are not high enough to control HIV and the participant
      can swallow tablets, hard gel capsules, or the contents of hard gel capsules with food or
      milk, the participant will begin taking SQV as part of his or her drug regimen and enter Step
      2. After two weeks of taking SQV, participants will again undergo PK testing at Week 6. Based
      on these test results, the dose of SQV will then be increased, decreased, or maintained.
      Participants who do not add SQV to their regimen will continue taking LPV/r for the remainder
      of the study and stay in Step 1. If the PK test indicates SQV blood concentrations are
      sufficient, the participant will remain in Step 2. If the PK test indicates SQV blood
      concentrations are too low, the SQV dose will be increased and the participant will enter
      Step 3. After 2 weeks of taking elevated doses of SQV, participants will undergo PK testing
      at Week 10. If the PK test indicates that SQV blood concentrations are too high, the SQV dose
      will be decreased. At Week 14, participants who receive a reduced SQV dose will again undergo
      PK testing to verify that SQV blood concentrations are optimal.

      Participants will have study visits at Weeks 2, 4, 6, 7, and 8, then every 4 weeks through
      the end of the study at Week 48. Study visits will include a physical exam, health history
      assessment, and blood collection. Blood collection for PK studies will occur at selected
      visits. Study visits at Weeks 2 and 12 will include an electrocardiogram (ECG or EKG).
    

Intervention name(s): Lopinavir/ritonavir; Saquinavir
Intervention type(s): Drug; Drug
Intervention MeSH terms: Ritonavir; Lopinavir; Saquinavir
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dose Intensification; Pharmacokinetic Sampling; Treatment Experienced; Child