Dyslipidemia, HIV
Conditions
Keywords
HIV-infected patients with dyslipidemia and receiving atazanavir/ritonavir
Brief summary
Dyslipidemia as a risk factor for cardiovascular disease (CVD) is an increasing problem in HIV-infected patients who are on antiretroviral therapy especially protease inhibitors including atazanavir. Pitavastatin is a new HMG-CoA reductase inhibitor with lesser drug-drug interactions and demonstrable efficacy in decreasing lipid levels in non HIV-infected individuals. The study was conducted as a randomized, double-blind, crossover study comparing the safety and efficacy of pitavastatin versus placebo in HIV-infected patients with dyslipidemia and receiving atazanavir/ritonavir. Patients were randomized to receive either placebo or pitavastatin for 12 weeks, underwent a 2-week washout period, and then were given the other treatment for an additional 12 weeks. Patients were observed for lipid profiles including total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL); and the side effects including clinical and laboratory (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatinine phosphokinase (CPK)). The follow-up visits were every 4 weeks until the end of the study.
Interventions
DRUGpitavastatin
Treatment A = administration pitavastatin for 12 weeks
DRUGplacebo
Treatment B = administration placebo for 12 weeks
Sponsors
Ramathibodi Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* aged ≥18 years * able to provide informed consent * had confirmed HIV infection * on ART including atazanavir 300 mg and ritonavir 100 mg each day in the regimens that were not changed within 12 weeks before the randomization * patients who had cholesterol level between 200 and 500 and LDL between 130 and 400 mg/dL without any lipid-lowering agent or discontinued the lipid-lowering agent at least 1 month prior to randomization
Exclusion criteria
* had the history of pitavastatin and/or the constituent of the drugs allergy * known history of myocardial infarction and/or ischemic stroke within 1 month prior to the randomization that would be endangered if we stopped the previous lipid-lowering agent before the enrollment * abnormal AST and ALT with level ≥5 times in asymptomatic patients or ≥3 times of upper normal limit (UNL) in symptomatic patients * pregnancy or breastfeeding * on cyclosporine which had major drug interactions with pitavastatin * patients who denied to join the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | 12 weeks | Efficacy was measured by level of TC, TG, LDL, and HDL that decreased after pitavastatin treatment. Pitavastatin was considered efficient when it could decrease TC, TG, LDL, or HDL significantly compared to placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Pitavastatin in HIV-infected Patients | 12 weeks | Safety clinical was defined by FDA; grade 1 mild symptoms; grade 2 moderate symptoms with limiting age-appropriate IADL; grade 3 severe symptoms with limiting self-care ADL, But not immediately life-threatening; grade 4 life-threatening consequences; and grade 5 death related to adverse event. Safety laboratory evaluation was determined safe if AST, ALT, and/or CPK level was not increased significantly comparing pitavastatin to placebo. |
Participant flow
Pre-assignment details
All subjects received all 2 treatments in a randomly assigned order. The treatments were: Treatment A: pitavastatin; Treatment B: placebo. The sequences were Treatments AB, BA.
Participants by arm
| Arm | Count |
|---|---|
| Treatment A, B Treatment visits were separated by a 2-week washout period. Treatment A = administration pitavastatin for 12 weeks; Treatment B = administration placebo for 12 weeks | 12 |
| Treatment B, A Treatment visits were separated by a 2-week washout period. Treatment B = administration placebo for 12 weeks; Treatment A = administration pitavastatin for 12 weeks | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Treatment A, B | Treatment B, A | Total |
|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 10.6 | 46.7 years STANDARD_DEVIATION 6.8 | 48.1 years STANDARD_DEVIATION 1.8 |
| Antiretroviral regimens combined with ATV/r No TDF in backbone | 5 participants | 4 participants | 9 participants |
| Antiretroviral regimens combined with ATV/r TDF + FTC/3TC | 5 participants | 6 participants | 11 participants |
| Antiretroviral regimens combined with ATV/r TDF + other NRTIs (exclude FTC/3TC) | 2 participants | 2 participants | 4 participants |
| Baseline CD4 cell counts | 641.9 cells/mm3 STANDARD_DEVIATION 196.5 | 718.1 cells/mm3 STANDARD_DEVIATION 181.2 | 680 cells/mm3 STANDARD_DEVIATION 189 |
| Baseline Creatinine | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 0.9 mg/dL STANDARD_DEVIATION 0.2 |
| Baseline Fasting blood sugar | 100.8 mg/dL STANDARD_DEVIATION 10.1 | 97.1 mg/dL STANDARD_DEVIATION 10.5 | 98.9 mg/dL STANDARD_DEVIATION 10.2 |
| Body mass index | 23.8 kg/m2 STANDARD_DEVIATION 2.7 | 22.5 kg/m2 STANDARD_DEVIATION 3.4 | 23.2 kg/m2 STANDARD_DEVIATION 3.1 |
| Cardiovascular risk factors <2 | 7 participants | 11 participants | 18 participants |
| Cardiovascular risk factors > or equal to 2 | 5 participants | 1 participants | 6 participants |
| Duration of ATV/r use | 42 months | 36 months | 36 months |
| HIV viral load <40 copies/mL | 12 participants | 11 participants | 23 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 14 Participants |
| Underlying conditions Chronic hepatitis B and C virus infection | 2 participants | 2 participants | 4 participants |
| Underlying conditions Dyslipidemia | 4 participants | 2 participants | 6 participants |
| Underlying conditions No | 4 participants | 8 participants | 12 participants |
| Underlying conditions Others | 2 participants | 0 participants | 2 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 0 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir
Efficacy was measured by level of TC, TG, LDL, and HDL that decreased after pitavastatin treatment. Pitavastatin was considered efficient when it could decrease TC, TG, LDL, or HDL significantly compared to placebo.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL after 12 weeks of treatment | 45.3 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at 8 weeks after treatment | 44.9 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at baseline | 239.9 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 8 weeks after treatment | 202.3 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at baseline | 282 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 12 weeks after treatment | 207 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at baseline | 144.7 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 8 weeks after treatment | 250.8 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at baseline | 43 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 12 weeks after treatment | 351.3 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 4 weeks after treatment | 201.3 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at 8 weeks after treatment | 111.5 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 4 weeks after treatment | 246.5 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL after 12 weeks of treatment | 113.2 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at 4 weeks after treatment | 43.5 mg/dL |
| Treatment A | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at 4 weeks after treatment | 111.6 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at 4 weeks after treatment | 43.5 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 8 weeks after treatment | 334 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 8 weeks after treatment | 255.2 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at 8 weeks after treatment | 145.1 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at 8 weeks after treatment | 43.7 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 12 weeks after treatment | 246.3 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 12 weeks after treatment | 279.1 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL after 12 weeks of treatment | 145.6 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL after 12 weeks of treatment | 44.2 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at baseline | 257.6 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at baseline | 350 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at baseline | 146.3 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | HDL at baseline | 44.8 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TC at 4 weeks after treatment | 246.6 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | LDL at 4 weeks after treatment | 142.5 mg/dL |
| Treatment B | Efficacy of Pitavastatin in HIV-infected Patients With Dyslipidemia and Receiving Atazanavir/Ritonavir | TG at 4 weeks after treatment | 292.5 mg/dL |
p-value: <0.05Mixed Models Analysis
Secondary
Safety of Pitavastatin in HIV-infected Patients
Safety clinical was defined by FDA; grade 1 mild symptoms; grade 2 moderate symptoms with limiting age-appropriate IADL; grade 3 severe symptoms with limiting self-care ADL, But not immediately life-threatening; grade 4 life-threatening consequences; and grade 5 death related to adverse event. Safety laboratory evaluation was determined safe if AST, ALT, and/or CPK level was not increased significantly comparing pitavastatin to placebo.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment A | Safety of Pitavastatin in HIV-infected Patients | AST at baseline | 38.2 U/L |
| Treatment A | Safety of Pitavastatin in HIV-infected Patients | ALT at baseline | 64.6 U/L |
| Treatment A | Safety of Pitavastatin in HIV-infected Patients | AST at 12 weeks after treatment | 39.5 U/L |
| Treatment A | Safety of Pitavastatin in HIV-infected Patients | ALT at 12 weeks after treatment | 64.2 U/L |
| Treatment B | Safety of Pitavastatin in HIV-infected Patients | ALT at 12 weeks after treatment | 72.5 U/L |
| Treatment B | Safety of Pitavastatin in HIV-infected Patients | AST at baseline | 36.3 U/L |
| Treatment B | Safety of Pitavastatin in HIV-infected Patients | AST at 12 weeks after treatment | 40.75 U/L |
| Treatment B | Safety of Pitavastatin in HIV-infected Patients | ALT at baseline | 58.9 U/L |