MedPath

Safety of Saquinavir and High Doses of Lopinavir/Ritonavir in Children With HIV

Phase 1
Completed
Conditions
HIV Infections
Registration Number
NCT00084058
Lead Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Brief 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).

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
26
Inclusion Criteria
  • HIV infected
  • HIV RNA viral load greater than 5,000 copies/ml
  • At least 6 months of continuous therapy with a protease inhibitor (PI) prior to study entry
  • No change in antiretroviral therapy since genotypic resistance testing
  • Genotypic resistance testing indicating a primary protease mutation at position 32, 47, 48, 50, 82, or 84 and at least three other mutations in positions 10, 20, 24, 30, 32, 33, 36, 46, 47, 48, 50, 53, 54, 71, 73, 77, 82, 84, or 90 OR phenotypic resistance testing, within 6 months of screening while on a failing regimen, indicating at least a fivefold increase in LPV as compared to wild type HIV
  • Parent or legal guardian willing to provide informed consent
  • If sexually active, agree to use acceptable methods of contraception
  • Have a telephone, pager, or other method of reliable communication with study staff
  • Able and willing to swallow study medications
Exclusion Criteria
  • Any drug toxicity greater than Grade 3 at screening
  • Certain abnormal laboratory values
  • Acute opportunistic or serious bacterial infection requiring treatment
  • Chemotherapy for active cancer
  • Any significant diseases (other than HIV infection) that may, in the opinion of the investigator, interfere with the study
  • Require certain medications
  • History of heart problems
  • Family history of prolonged QTc-Interval Syndrome or prolonged QTc-interval at study entry
  • Pregnancy or breastfeeding

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Primary Outcome Measures
NameTimeMethod
dose-limiting toxicity, defined as adverse events of Grade 3 or greater attributable to study drug and require dose reduction or interruption but are not judged to be life-threatening by the protocol team
Life-threatening adverse events attributable to study drugs
Secondary Outcome Measures
NameTimeMethod
immunologic success, defined as a CD4% increase from baseline of 5% or more points by Week 24
virologic success, defined by optimal response (undetectable viral load) at Week 24 or adequate response (0.75 log drop in viral load or more) from baseline to Week 24
virologic failure, defined as an inadequate (less than 0.75 log drop in viral load) or suboptimal (confirmed viral load of greater than 400 copies/ml) response at Week 24
minimal criterion for overall success, defined as a 0.75 log drop in viral load or more or 5% point increase in CD4% from baseline to Week 24
Pharmacological success, defined as achieving an inhibitory quotient (IQ) of 15 after 2 weeks on high-dose LPV/r without life-threatening or dose-limiting toxicity

Trial Locations

Locations (15)

St. Jude/UTHSC CRS

πŸ‡ΊπŸ‡Έ

Memphis, Tennessee, United States

Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS

πŸ‡΅πŸ‡·

San Juan, Puerto Rico

Strong Memorial Hospital Rochester NY NICHD CRS

πŸ‡ΊπŸ‡Έ

Rochester, New York, United States

Long Beach Memorial Med. Ctr., Miller Children's Hosp.

πŸ‡ΊπŸ‡Έ

Long Beach, California, United States

Harlem Hosp. Ctr. NY NICHD CRS

πŸ‡ΊπŸ‡Έ

New York, New York, United States

Nyu Ny Nichd Crs

πŸ‡ΊπŸ‡Έ

New York, New York, United States

San Juan City Hosp. PR NICHD CRS

πŸ‡΅πŸ‡·

San Juan, Puerto Rico

UAB, Dept. of Ped., Div. of Infectious Diseases

πŸ‡ΊπŸ‡Έ

Birmingham, Alabama, United States

UCSF Pediatric AIDS CRS

πŸ‡ΊπŸ‡Έ

San Francisco, California, United States

Chicago Children's CRS

πŸ‡ΊπŸ‡Έ

Chicago, Illinois, United States

Tulane/LSU Maternal/Child CRS

πŸ‡ΊπŸ‡Έ

New Orleans, Louisiana, United States

Johns Hopkins Hosp. & Health System - Dept. of Peds., Div. of Infectious Diseases

πŸ‡ΊπŸ‡Έ

Baltimore, Maryland, United States

HMS - Children's Hosp. Boston, Div. of Infectious Diseases

πŸ‡ΊπŸ‡Έ

Boston, Massachusetts, United States

Jacobi Med. Ctr.

πŸ‡ΊπŸ‡Έ

Bronx, New York, United States

DUMC Ped. CRS

πŸ‡ΊπŸ‡Έ

Durham, North Carolina, United States

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