IMPAACT P1063: Safety and Effectiveness of Atorvastatin in HIV Infected Children and Adolescents With Hyperlipidemia

Study Overview
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Brief Summary
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Treatment of HIV with combination antiretroviral regimens frequently results in the suppression of HIV viral load, significant immune recovery, and delayed disease progression. However, treatment with these regimens, particularly protease inhibitors (PIs), has been associated with significant increases in cholesterol and triglycerides in HIV-infected adults and children. The purpose of this study was to evaluate the safety and effectiveness of escalating doses of atorvastatin, a FDA-approved drug which lowers cholesterol and triglyceride levels, in HIV-infected children receiving stable antiretroviral regimens.

Detailed Description
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Antiretroviral regimens, particularly those containing PIs, often cause hyperlipidemia, which is an increase in the amount of fat (such as cholesterol and triglycerides) in the blood. These increases can lead to heart disease and pancreatitis. Although the mechanism by which PIs cause hyperlipidemia is not clearly understood, there are medications to combat this side effect. The primary purpose of this study was to evaluate the safety and effectiveness of escalating doses of atorvastatin, based on low-density lipoprotein cholesterol (LDL-C) levels, in HIV-infected children receiving stable antiretroviral therapy. Participants were assigned to one of two groups based on age (10 to 14 years or 15 to 23 years) and were treated for a maximum of 48 weeks. The first six participants enrolled in the study were in the 15 to 23 year old age group. Once safety data through week 8 on these 6 participants was analyzed, the remaining participants were enrolled. All participants received atorvastatin in combination with a stable antiretroviral regimen. Each participant was followed independently according to a dose escalation algorithm for atorvastatin. Participants began dosing at 10 mg daily. If efficacy criteria were not met, dosing increased to 20 mg daily at week 8. Since dose escalations were done within subject, safety and efficacy rates were presented for the dose-escalation strategy overall and not for individual doses. Atorvastatin was provided by the study, but antiretrovirals were not. Study visits occurred at study entry and weeks 4, 8, 12, 24, 36, and 48. Safety labs were collected at all study visits. Blood collection for lipid measurements occurred at weeks 4, 12, 24 and 48.

Official Title
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Phase I/II Safety and Efficacy Investigation of Atorvastatin for Treatment of PI-Associated Increased LDL Cholesterol in HIV-Infected Children and Adolescents

Conditions
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HIV Infections, Hyperlipidemia

Intervention / Treatment
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* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of HIV-1 infection CD4 % of at least 15 at screening HIV-1 viral load of less than 10,000 copies/ml at screening On a stable antiretroviral therapy regimen for at least 6 months Tanner stage of 2 or higher At least two LDL-C measurements of 130 mg/dL or higher over the 6 months prior to screening and after documented attempts at modifying diet and other risk factors. More information on this criterion can be found in the protocol. Able to fast overnight for 8 hours Negative pregnancy test at screening Agree to use two appropriate forms of contraception (female participants). More information on this criterion can be found in the protocol. Exclusion Criteria: Certain abnormal laboratory values Any laboratory or unresolved clinical toxicity of Grade 3 or higher Unlikely to remain on current antiretroviral therapy for at least six months after study entry Use of statin, fibrate, or niacin within 3 months prior to study entry Evidence of chronic ongoing myositis or history of myopathy or neuromuscular disorder Symptomatic peripheral neuropathy within 6 months prior to study entry Pharmacologic treatment for depression or other mental disorder excluding Attention Deficit Disorder within 30 days prior to study entry Presence of an active CDC Stage C opportunistic infection or serious bacterial infection requiring therapy within 2 weeks prior to screening. Chemotherapy for malignancy within 3 months prior to study entry Hepatitis B Surface Antigen positive Hepatitis C viremia Insulin-dependent diabetes mellitus Required treatment with an agent contraindicated with either atorvastatin or PIs. More information on this criterion can be found in the protocol. Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 23 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Age 10 to 14<br>Participants ages 10 to 14 years receiving oral atorvastatin for 48 weeks while on a stable antiretroviral regimen | Drug: Atorvastatin<br>* 10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.<br>* Other names: Lipitor;|
| Experimental: Age 15 to 23<br>Participants ages 15 to 23 years receiving oral atorvastatin for 48 weeks while on a stable antiretroviral regimen | Drug: Atorvastatin<br>* 10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.<br>* Other names: Lipitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE) | AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the core study team. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher. | Study entry to weeks 12, 24, and 48 | 
| Percentage of Participants Experiencing at Least One Adverse Event (AE) | AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher. | Study entry to weeks 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Intention to Treat) | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Data Available) | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Per Protocol) | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria and Did Not Experience a Primary Safety Endpoint Attributable to Study Drug | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by Age Group | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by NNRTI Treatment | Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week. | Study entry and weeks 4, 12, 24, and 48 | 
| Percent Change in LDL Cholesterol (LDL-C) From Study Entry |  | Study entry and weeks 4, 12, 24, and 48 | 
| Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE) by Age Group | AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the core study team. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher. | Study entry to weeks 12, 24, and 48 | 
| Percentage of Participants Experiencing at Least One Adverse Event (AE) by Age Group | AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher. | Study entry to weeks 12, 24, and 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Fasting Total Cholesterol (TC) From Study Entry |  | Study entry and weeks 4, 12, 24, and 48 | 
| Percent Change in Triglycerides (TG) From Study Entry |  | Study entry and weeks 4, 12, 24, and 48 | 
| Percent Change in HDL-cholesterol (HDL-C) From Study Entry |  | Study entry and weeks 4, 12, 24, and 48 | 
| Percent Change in Apolipoprotein A1 (Apo A-1) From Study Entry |  | Study entry and weeks 12, 24, and 48 | 
| Percent Change in Apolipoprotein B (Apo B) From Study Entry |  | Study entry and weeks 12, 24, and 48 | 
| Percent Change in High-sensitivity CRP (Hs-CRP) From Study Entry |  | Study entry and weeks 12, 24, and 48 | 
| Percent Change in Interleukin 6 (IL-6) From Study Entry |  | Study entry and weeks 12, 24, and 48 | 
| Percentage of Participants With Undetectable Plasma HIV-1 RNA | Undetectable is defined as plasma HIV-1 RNA below the lower limit of quantification of the assay used. | Study entry and weeks 12, 24, and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced