HIV Infections
Conditions
Keywords
HIV, Kaletra, Reyataz, Insulin sensitivity, Lipids, Body Composition, Receiving Kaletra, Treatment Experienced
Brief summary
To study the effects of switching from Kaletra to Boosted Reyataz on glucose, lipids and fat in HIV-infected patients.
Detailed description
The primary objective of this study is to determine tissue specific glucose trafficking in patients before and after switching from a regimen containing Lopinavir/ritonavir (LPV/r) to one containing atazanavir/ritonavir (ATV/r). Secondary outcome measures of interest will include insulin sensitivity determined by clamp testing, and lipid metabolism and hepatic glucose production assessed using stable isotope techniques. We hypothesize that switching protease inhibitor (PI) to ATV/r from LPV/r will result in direct increases in glucose uptake in muscle and visceral adipose tissue in association with improvements in overall whole body insulin sensitivity compared to remaining on LPV/r. We will complete a prospective randomized trial of Human Immunodeficiency Virus (HIV) infected patients who have been on a stable antiretroviral (ARV) regimen containing LPV/r for at least 6 months and who will be randomized to either switch to a regimen containing ATV/r or remain on LPV/r for 6 months. Each subject will complete Positron Emission Tomography (PET) 18-fluorodeoxyglucose (FDG) imaging during a hyperinsulinemic clamp study at baseline and 6 months after randomization.
Interventions
atazanavir 300mg + ritonavir 100mg once daily
DRUGlopinavir/ritonavir
patient remains on their pre-study dose of lopinavir/ritonavir
Sponsors
Bristol-Myers Squibb
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Previously diagnosed HIV infection 2. Age between 18-65 years 3. Stable antiviral regimen containing at least 2 nucleoside reverse transcriptase inhibitors (NRTI's) and LPV/r for ³ 6 mos 4. CD4 count \> 400 cell/mm3 5. Metabolic complication as indicated by one or more of hyperinsulinemia (fasting insulin \>= 15 mIU/ml), hypercholesteremia (fasting total cholesterol \>= 200 mg/dL), hypertriglyceridemia (fasting triglycerides \>= 150 mg/dL), or treatment with a lipid lowering medication.
Exclusion criteria
1. Hemoglobin \< 11.0 g/dL 2. History of Diabetes Mellitus 3. Currently on medication for Diabetes 4. Therapy with glucocorticoid, growth hormone or other anabolic agents currently or within the past 3 months 5. Current substance abuse, including alcohol, cocaine and/or heroin 6. Any contraindication to ATV/r or known allergy to ATV 7. Concurrent therapy with: Bepridil; cisapride; ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine); indinavir; irinotecan; lovastatin; midazolam; pimozide; proton pump inhibitors (esomeprazole, lansoprazole, omeprazole); rifampin; simvastatin; St John's wort; or triazolam 8. New or serious opportunistic infection in the past 3 months 9. Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Trafficking | 6 months | 6 month mean and standard deviation for glucose uptake into anterior thigh muscle as measured by FDG/PET scanning during euglycemic hyperinsulinemic clamp. During the hyperinsulinemic conditions of the clamp, glucose and 18-FDG \[labeled glucose\] are taken up by muscle. The quantity of 18-FDG taken up is measured by the PET scan. Although there are no well-accepted norms for this measurement, a higher value indicates that more glucose is being taken up by (or trafficked to) muscle. Increased uptake of glucose indicates increased muscle insulin sensitivity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Glucose | 6 months | 6 month mean and standard deviation for fasting glucose. |
| Lipid Metabolism - Serum Triglyceride | 6 months | 6 month mean and standard deviation for serum triglyceride. |
| Body Composition - Visceral Adipose Tissue | 6 months | 6 month mean and standard deviation for visceral adipose tissue (VAT) as measured by single slice computed tomography (CT) scan at the L4 pedicle (pedicle of 4th lumbar vertebra). |
| Insulin Sensitivity | 6 months | 6 month mean and standard deviation for insulin-stimulated glucose uptake (M) per unit insulin at 120 minutes as measured by euglycemic hyperinsulinemic clamp. |
| Liver Enzymes -- Aspartate Aminotransferase (AST) | 6 months | 6 month mean and standard deviation for AST. |
| Liver Enzymes -- Alanine Aminotransferase (ALT) | 6 months | 6 month mean and standard deviation for ALT. |
| Total Bilirubin | 6 months | 6 month mean and standard deviation for total bilirubin. |
| Immune Parameters -- CD4 Count | 6 months | 6 month mean and standard deviation for CD4+ count. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited through information given to HIV-care providers, postings in HIV-community organizations, newspaper advertisements, and the Massachusetts General Hospital research patient data registry. Recruitment began in March, 2006, and continued through May, 2008.
Pre-assignment details
After screening visit to determine eligibility, subjects were asked to continue their current antiretroviral medications until the baseline visit, immediately after which they were randomized to continue lopinavir/ritonavir or switch to atazanavir/ritonavir.
Participants by arm
| Arm | Count |
|---|---|
| Boosted Reyataz (ATV/r) Boosted Reyataz (300mg atazanavir + 100mg ritonavir) | 7 |
| Continue Kaletra (LPV/r) Kaletra (pre-study dose) | 8 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Continue Kaletra (LPV/r) | Boosted Reyataz (ATV/r) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 7 Participants | 15 Participants |
| Age Continuous | 50 years STANDARD_DEVIATION 6 | 46 years STANDARD_DEVIATION 8 | 48 years STANDARD_DEVIATION 7 |
| Region of Enrollment United States | 8 participants | 7 participants | 15 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 1 / 8 |
| serious Total, serious adverse events | 2 / 7 | 0 / 8 |
Outcome results
Primary
Glucose Trafficking
6 month mean and standard deviation for glucose uptake into anterior thigh muscle as measured by FDG/PET scanning during euglycemic hyperinsulinemic clamp. During the hyperinsulinemic conditions of the clamp, glucose and 18-FDG \[labeled glucose\] are taken up by muscle. The quantity of 18-FDG taken up is measured by the PET scan. Although there are no well-accepted norms for this measurement, a higher value indicates that more glucose is being taken up by (or trafficked to) muscle. Increased uptake of glucose indicates increased muscle insulin sensitivity.
Time frame: 6 months
Population: Only data from subjects with 0 and 6 month Positron Emission Tomography (PET) scans were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Glucose Trafficking | 26.7 umol/kg/min | Standard Deviation 8.1 |
| Continue Kaletra (LPV/r) | Glucose Trafficking | 24.4 umol/kg/min | Standard Deviation 17.7 |
Comparison: Initial samples size of N=16 calculated to provide 80% power to detect a 30% change in muscle glucose uptake between groups. Student's t-test used to compare change from baseline and determine treatment effect (net difference over time between the ATV/r vs. LPV/r groups).p-value: 0.035t-test, 2 sided
Secondary
Body Composition - Visceral Adipose Tissue
6 month mean and standard deviation for visceral adipose tissue (VAT) as measured by single slice computed tomography (CT) scan at the L4 pedicle (pedicle of 4th lumbar vertebra).
Time frame: 6 months
Population: Data from participants with 0 \& 6 month data analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Body Composition - Visceral Adipose Tissue | 91 square centimeters | Standard Deviation 34 |
| Continue Kaletra (LPV/r) | Body Composition - Visceral Adipose Tissue | 167 square centimeters | Standard Deviation 61 |
p-value: 0.047t-test, 2 sided
Secondary
Fasting Glucose
6 month mean and standard deviation for fasting glucose.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Fasting Glucose | 84 mg/dL | Standard Deviation 7 |
| Continue Kaletra (LPV/r) | Fasting Glucose | 90 mg/dL | Standard Deviation 21 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.002Repeated Measures ANCOVA
Secondary
Immune Parameters -- CD4 Count
6 month mean and standard deviation for CD4+ count.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Immune Parameters -- CD4 Count | 432 cells/microL | Standard Deviation 192 |
| Continue Kaletra (LPV/r) | Immune Parameters -- CD4 Count | 688 cells/microL | Standard Deviation 230 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.72Repeated Measures ANCOVA
Secondary
Insulin Sensitivity
6 month mean and standard deviation for insulin-stimulated glucose uptake (M) per unit insulin at 120 minutes as measured by euglycemic hyperinsulinemic clamp.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Insulin Sensitivity | 39.0 umol/kg/min per uU/mL insulin | Standard Deviation 17.7 |
| Continue Kaletra (LPV/r) | Insulin Sensitivity | 49.2 umol/kg/min per uU/mL insulin | Standard Deviation 22.5 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs. LPV/r)p-value: 0.12Repeated measures ANCOVA
Secondary
Lipid Metabolism - Serum Triglyceride
6 month mean and standard deviation for serum triglyceride.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Lipid Metabolism - Serum Triglyceride | 147 mg/dL | Standard Deviation 92 |
| Continue Kaletra (LPV/r) | Lipid Metabolism - Serum Triglyceride | 209 mg/dL | Standard Deviation 87 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.02Repeated measures ANCOVA
Secondary
Liver Enzymes -- Alanine Aminotransferase (ALT)
6 month mean and standard deviation for ALT.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Liver Enzymes -- Alanine Aminotransferase (ALT) | 61 U/L | Standard Deviation 29 |
| Continue Kaletra (LPV/r) | Liver Enzymes -- Alanine Aminotransferase (ALT) | 65 U/L | Standard Deviation 34 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.004Repeated Measures Ancova
Secondary
Liver Enzymes -- Aspartate Aminotransferase (AST)
6 month mean and standard deviation for AST.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Liver Enzymes -- Aspartate Aminotransferase (AST) | 39 U/L | Standard Deviation 29 |
| Continue Kaletra (LPV/r) | Liver Enzymes -- Aspartate Aminotransferase (AST) | 42 U/L | Standard Deviation 29 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.22Repeated Measures ANCOVA
Secondary
Total Bilirubin
6 month mean and standard deviation for total bilirubin.
Time frame: 6 months
Population: Repeated measures analysis using all available data points for each participant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boosted Reyataz (ATV/r) | Total Bilirubin | 2.8 mg/dL | Standard Deviation 2.7 |
| Continue Kaletra (LPV/r) | Total Bilirubin | 0.6 mg/dL | Standard Deviation 0.3 |
Comparison: Repeated measures ANCOVA, controlling for baseline values, used to assess treatment effect of the randomization over 6 months (net difference over time between ATV/r vs.LPV/r).p-value: 0.0002Repeated Measures ANCOVA