Cardiovascular Diseases, HIV
Conditions
Keywords
HIV, Cardiovascular Disease, Myocardial Infarction, Inflammation, Statin, Computerized Tomography, Cholesterol, COVID-19
Brief summary
People with HIV are at risk for cardiovascular disease (CVD). This study evaluated the use of pitavastatin to reduce the risk of CVD in adults with HIV on antiretroviral therapy (ART). The REPRIEVE trial consisted of two parallel identical protocols: * REPRIEVE (A5332) was funded by the NHLBI, with additional infrastructure support provided by the NIAID, and was conducted in U.S and select international sites (approximately 120 sites in 11 countries). * REPRIEVE (EU5332) was co-sponsored by NEAT ID and MGH, and was conducted at 13 sites in Spain.
Detailed description
There are few strategies to prevent CVD in people with HIV (PWH), even though they are at high risk for developing CVD. Statin medications are used to lower cholesterol and may be effective at reducing the risk of CVD in PWH. The purpose of this study was to evaluate the use of pitavastatin to reduce the risk of CVD in PWH on ART. This study enrolled PWH who were on any ART regimen (ART was not provided by the study) for at least 6 months before study entry and were at low to moderate risk of CVD using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline thresholds for recommended statin initiation. Participants were randomly assigned to receive 4 mg of pitavastatin or placebo once a day for their entire study duration. Pitavastatin or placebo could be discontinued and clinically indicated statin therapy initiated at the discretion of the site investigator or the participant's care provider, with the intention of following the participant according to the intention-to-treat trial design. Study visits occurred at study entry and Months 1 and 4. Starting at Month 4, study visits occurred every 4 months for the rest of the study. Depending on when participants enrolled, they were in the study for a total of 4 to 8 years. Study visits included medical and medication history reviews, physical examinations, blood collections, assessments and questionnaires, urine collections (for some participants), and an electrocardiogram (ECG) (at study entry only). Participants at US sites had the option of enrolling in a substudy (Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of REPRIEVE \[A5333s\]). The substudy evaluated the effect of pitavastatin on the progression of non-calcified coronary atherosclerotic plaque (NCP) and inflammatory biomarkers in PWH. Participants in the substudy attended study visits at study entry and Months 4 and 24. The visits included questionnaires and assessments, a blood collection, and a coronary computed tomography angiography (CCTA). The Mechanistic Substudy closed to accrual on February 6, 2018, when its accrual target of 800 participants had been reached. Sites that enrolled participants into the Mechanistic Substudy are indicated with asterisk (\*) at the end of the institution names in the Contacts and Locations section. Participants enrolled in REPRIEVE from select study sites, including international sites, through December, 2017, were included in the REPRIEVE Kidney Function Objectives Cohort to evaluate the effects of pitavastatin on parameters of kidney function in the setting of HIV. These objectives include evaluating high risk groups and mechanisms driving kidney function decline in the setting of HIV. Women and men enrolled in REPRIEVE after February, 2016 were included in an observational cohort (REPRIEVE Women's Objectives Cohort) facilitating assessment of sex-specific mechanisms of CVD risk and risk reduction among PWH. This effort also included an evidence-based recruitment campaign to enhance women's participation in REPRIEVE. In response to the SARS-CoV-2 pandemic, a supplemental objective was added in 2020. To better understand how COVID-19 affects PWH and if pitavastatin may reduce the risk of serious COVID-19 disease, we evaluated interrelated but independent key topics including epidemiology, host factors, and protective strategies. Starting from April 2020, COVID-19 assessment was completed at each study visit, and blood was collected for COVID-19 biomarkers. The data and safety monitoring board (DSMB) recommended stopping the trial for efficacy at the second planned review on March 30, 2023, and concluded that no unexpected safety concerns had been reported. Following the DSMB action, participants were asked to return for the final study visit. All final visits were completed by August 21, 2023. We here present the results based on the final trial database, including the full follow-up out to closeout visits.
Interventions
DRUGPitavastatin
One tablet (4 mg) taken once daily, orally with or without food
DRUGPlacebo
One tablet taken once daily, orally with or without food
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Kowa Pharmaceuticals America, Inc.
Gilead Sciences
Massachusetts General Hospital
NEAT ID Foundation
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Individual with HIV-1 * Combination antiretroviral therapy (ART) for at least 180 days prior to study entry * CD4+ cell count greater than 100 cells/mm\^3 * Acceptable screening laboratories including: * Fasting low-density lipoprotein (LDL) cholesterol as follows: * If ASCVD risk score was less than 7.5%, LDL cholesterol must have been less than 190 mg/dL. * If ASCVD risk score was greater than or equal to 7.5% and less than or equal to 10%, LDL must have been less than 160 mg/dL. * If ASCVD risk score was greater than 10% and less than or equal to 15%, LDL must have been less than 130 mg/dL. * Participants with LDL less than 70 mg/dL were eligible regardless of the 10-year ASCVD risk score, in line with the ACC/AHA 2013 Prevention Guidelines. * Fasting triglycerides less than 500 mg/dL * Hemoglobin greater than or equal to 8 g/dL for female participants and greater than or equal to 9 g/dL for male participants * Glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m\^2 or creatinine clearance (CrCl) greater than or equal to 60 mL/min * Alanine aminotransferase (ALT) less than or equal to 2.5 x the upper limit of normal (ULN) * For persons with known chronic active hepatitis B or C, calculated fibrosis 4 score (FIB-4) must have been less than or equal to 3.25 * Ability and willingness of participant or legal representative to provide written informed consent
Exclusion criteria
* Clinical ASCVD, as defined by 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, including a previous diagnosis of any of the following: * Acute myocardial infarction (AMI) * Acute coronary syndromes * Stable or unstable angina * Coronary or other arterial revascularization * Stroke * Transient ischemic attack (TIA) * Peripheral arterial disease presumed to be of atherosclerotic origin * Current diabetes mellitus with LDL greater than or equal to 70 mg/dL * 10-year ASCVD risk score estimated by Pooled Cohort Equations greater than 15% * Active cancer within 12 months prior to study entry, except successfully treated non-melanomatous skin cancer and Kaposi sarcoma without visceral organ involvement * Known decompensated cirrhosis * History of myositis or myopathy with active disease in the 180 days prior to study entry * Known untreated symptomatic thyroid disease * History of allergy or severe adverse reaction to statins * Use of specific immunosuppressants or immunomodulatory agents including but not limited to tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, tumor necrosis factor (TNF)-alpha blockers or antagonists, azathioprine, interferon, growth factors, or intravenous immunoglobulin (IVIG) in the 30 days prior to study entry. * Current use of erythromycin, colchicine, or rifampin * Use of any statin drugs, gemfibrozil, or PCSK9 inhibitors in the 90 days prior to study entry * Current use of an investigational new drug that would be contraindicated * Serious illness or trauma requiring systemic treatment or hospitalization in the 30 days prior to study entry * Current pregnancy or breastfeeding * Alcohol or drug use that, in the opinion of the site investigator, would interfere with completion of study procedures * Other medical, psychiatric, or psychological condition that, in the opinion of the site investigator, would interfere with completion of study procedures and or adherence to study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Major Adverse Cardiovascular Event (MACE) | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | MACE is a composite of cardiovascular (CV) death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack (TIA), peripheral arterial ischemia, coronary, carotid or peripheral arterial revascularization, or death from an undetermined cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Cardiac Ischemia or Myocardial Infarction | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Cardiac ischemia or myocardial infarction component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Cerebrovascular Event (Stroke or TIA) | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Cerebrovascular event (stroke or TIA) component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Peripheral Arterial Ischemia | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Peripheral arterial ischemia component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Death From CV Causes | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | CV death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths and deaths from undetermined causes were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Death From CV or Undetermined Causes | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | CV or undetermined death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Change in LpPLA2 From Baseline | Entry and month 24. | Change in inflammatory biomarker LpPLA2 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Cardiac Catheterization or Revascularization | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Cardiac cardiac catheterization or revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Carotid or Cerebrovascular Revascularization | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Carotid or cerebrovascular revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Peripheral Arterial Revascularization | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Peripheral arterial revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of MACE or Death | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | A composite outcome including MACE and death from any cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Death (All-cause) | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Death from any cause. The incidence rates were estimated based on time to event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Non-CV Clinical Diagnoses | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | A composite of non-CV clinical diagnoses including: non-AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of the skin), AIDS-defining events (based on Centers for Disease Control and Prevention \[CDC\] 2014 classification), end-stage renal disease, and end-stage liver disease. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Non-AIDS-defining Cancer | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Non-AIDS-defining cancer (excluding basal cell and squamous cell carcinomas of the skin) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of AIDS-defining Event | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | AIDS-defining event component of the composite non-CV clinical diagnoses outcome. Events were captured based on the Centers for Disease Control and Prevention \[CDC\] 2014 classification. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: HsCRP Level | Entry and month 24. | Level of inflammatory marker high-sensitivity C-reactive protein (HsCRP). Censored values below or above the assay limit were imputed. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of End-Stage Renal Disease | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | End-stage renal disease (defined as initiation of dialysis or renal transplantation) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of End-Stage Liver Disease | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | End-stage liver disease (defined as cirrhosis or hepatic decompensation requiring hospitalization) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Soluble CD163 Level | Entry and month 24. | Level of immune biomarker soluble CD163. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Change in Soluble CD163 From Baseline | Entry and month 24. | Change in immune biomarker soluble CD163 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Non-fatal Serious Adverse Event | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of non-fatal serious adverse event was defined by International Conference on Harmonisation (ICH) criteria. Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Diabetes | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of diabetes was defined as new diagnosis of diabetes with initiation of anti-diabetic agent. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Myalgia, Muscle Weakness or Myopathy | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of myalgia, muscle weakness or myopathy which were grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Rhabdomyolysis | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of rhabdomyolysis which was grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Grade 3 or Higher ALT | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of Grade 3 or higher alanine transaminase (ALT). Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Adverse Event (AE) | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Safety analysis outcome measure of any AE. AE collection included events of grade ≥3, those that were serious (defined by International Conference on Harmonisation (ICH) criteria) or treatment-limiting, and targeted diagnosis of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Fasting Low-density Lipoprotein Cholesterol (LDL-C) | At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment. | LDL-C level was derived as LDL-C calculated according to the Friedewald formula at triglycerides ≤400 mg/dL, and direct LDL-C at triglycerides \>400 to \<500 mg/dL. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment. | Non-HDL cholesterol levels were calculated as total cholesterol minus HDL cholesterol. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of Serious COVID-19 | From January 1, 2020 through end of study; the median follow-up time was 3.3 years. | Serious COVID-19 was defined as COVID-19 that resulted in hospitalization or death or was life-threatening as per the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline E2A definition. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| Incidence Rate of COVID-19 | From January 1, 2020 through end of study; the median follow-up time was 3.3 years. | COVID-19 was defined as COVID-19 clinical diagnosis or positive test result (SARS-CoV-2 PCR or rapid antigen tests). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios (prescribed pitavastatin compared to placebo) from Poisson regression models, adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2 | Entry and Year 2. | NCP was defined as plaque voxels with attenuation of \<350. Change in NCP is expressed as absolute change from baseline (calculated as NCP volume at 2 years minus NCP volume at entry), based on quantitative read of the CT scan, whenever available. Participants without a quantitative read and no evidence of NCP based on the corresponding qualitative read were assigned a value of zero for the change. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2 | Entry and year 2. | Progression at Year 2 was defined as any progression/increase in NCP volume in participants with evidence of NCP at entry, or incident NCP in participants without evidence of NCP at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2 | Entry and year 2. | Total plaque includes all plaque voxels (noncalcified + calcified). Change in total plaque volume is expressed as absolute change from baseline (calculated as volume at 2 years minus volume at entry). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: LpPLA2 Level | Entry and month 24. | Level of inflammatory biomarker lipoprotein-associated phospholipase A2 (LpPLA2). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
| For Mechanistic Substudy: Change in HsCRP From Baseline | Entry and month 24. | Change in inflammatory biomarker hsCRP from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of MACE by Sex | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Subgroup analysis of the primary composite MACE outcome measure (as described above) by sex. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include sex and interaction of sex and treatment, to evaluate modification of statin effect. |
| Incidence Rate of MACE by Race | From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). | Subgroup analysis of the primary composite MACE outcome measure (as described above) by race. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include race and interaction of race and treatment, to evaluate modification of statin effect. |
Countries
Botswana, Brazil, Canada, Haiti, India, Peru, Puerto Rico, South Africa, Spain, Thailand, Uganda, United States, Zimbabwe
Participant flow
Recruitment details
Participants were enrolled from March 26, 2015 to July 31, 2019.
Pre-assignment details
4 inadvertent duplicate enrollments of the same person were excluded. The total enrollment number of 7769 represents unique participants enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Pitavastatin Participants received pitavastatin once a day for the entire time they were in study follow-up.
Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food | 3,888 |
| Placebo Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up.
Placebo: One tablet taken once daily, orally with or without food | 3,881 |
| Total | 7,769 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 258 | 249 |
| Overall Study | Other | 5 | 3 |
| Overall Study | Physician Decision | 25 | 25 |
| Overall Study | Site Closure | 15 | 19 |
| Overall Study | Unable to get to clinic | 69 | 60 |
| Overall Study | Withdrawal by Subject | 315 | 324 |
Baseline characteristics
| Characteristic | Pitavastatin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50 years | 50 years | 50 years |
| Age, Customized 40-49 years | 1842 Participants | 1888 Participants | 3730 Participants |
| Age, Customized 50-59 years | 1712 Participants | 1649 Participants | 3361 Participants |
| Age, Customized ≥60 years | 334 Participants | 344 Participants | 678 Participants |
| Atherosclerotic Cardiovascular Disease (ASCVD) risk score 0 - <2.5% | 1096 Participants | 1060 Participants | 2156 Participants |
| Atherosclerotic Cardiovascular Disease (ASCVD) risk score ≥10% | 288 Participants | 275 Participants | 563 Participants |
| Atherosclerotic Cardiovascular Disease (ASCVD) risk score 2.5 - <5% | 1030 Participants | 1025 Participants | 2055 Participants |
| Atherosclerotic Cardiovascular Disease (ASCVD) risk score 5 - <7.5% | 934 Participants | 960 Participants | 1894 Participants |
| Atherosclerotic Cardiovascular Disease (ASCVD) risk score 7.5 - 10% | 540 Participants | 561 Participants | 1101 Participants |
| CD4 cell count ≤500 cells/mm^3 | 1257 Participants | 1253 Participants | 2510 Participants |
| CD4 cell count >500 cells/mm^3 | 2631 Participants | 2628 Participants | 5259 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 366 Participants | 332 Participants | 698 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1575 Participants | 1611 Participants | 3186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 18 Participants | 34 Participants |
| Global burden of disease (GBD) region High income | 2044 Participants | 2051 Participants | 4095 Participants |
| Global burden of disease (GBD) region Latin America and Caribbean | 709 Participants | 714 Participants | 1423 Participants |
| Global burden of disease (GBD) region South Asia | 246 Participants | 258 Participants | 504 Participants |
| Global burden of disease (GBD) region Southeast or East Asia | 304 Participants | 286 Participants | 590 Participants |
| Global burden of disease (GBD) region Sub-Saharan Africa | 585 Participants | 572 Participants | 1157 Participants |
| HIV-1 RNA ≥400 copies/mL | 63 Participants | 67 Participants | 130 Participants |
| HIV-1 RNA <LLQ | 2641 Participants | 2609 Participants | 5250 Participants |
| HIV-1 RNA LLQ - <400 copies/mL | 305 Participants | 312 Participants | 617 Participants |
| Mechanistic Substudy: NCP Volume | 52.3 mm^3 STANDARD_DEVIATION 193.5 | 57.7 mm^3 STANDARD_DEVIATION 109.2 | 55.1 mm^3 STANDARD_DEVIATION 156.5 |
| Mechanistic Substudy: Presence of Non-calcified Plaque (NCP) NCP not present | 189 Participants | 184 Participants | 373 Participants |
| Mechanistic Substudy: Presence of Non-calcified Plaque (NCP) NCP present | 132 Participants | 139 Participants | 271 Participants |
| Mechanistic Substudy: Total Plaque Volume | 65.6 mm^3 STANDARD_DEVIATION 211.7 | 72.2 mm^3 STANDARD_DEVIATION 135.9 | 69.0 mm^3 STANDARD_DEVIATION 176.8 |
| Nadir CD4 cell count 200 - 349 cells/mm^3 | 1019 Participants | 1022 Participants | 2041 Participants |
| Nadir CD4 cell count <200 cells/mm^3 | 1890 Participants | 1911 Participants | 3801 Participants |
| Nadir CD4 cell count ≥350 cells/mm^3 | 839 Participants | 825 Participants | 1664 Participants |
| Nadir CD4 cell count Unknown | 140 Participants | 123 Participants | 263 Participants |
| Pre-existing diabetes | 24 Participants | 14 Participants | 38 Participants |
| Race/Ethnicity, Customized Asian | 571 Participants | 567 Participants | 1138 Participants |
| Race/Ethnicity, Customized Black | 1569 Participants | 1639 Participants | 3208 Participants |
| Race/Ethnicity, Customized Other | 384 Participants | 335 Participants | 719 Participants |
| Race/Ethnicity, Customized White | 1364 Participants | 1340 Participants | 2704 Participants |
| Region of Enrollment Botswana | 145 participants | 136 participants | 281 participants |
| Region of Enrollment Brazil | 546 participants | 553 participants | 1099 participants |
| Region of Enrollment Canada | 60 participants | 71 participants | 131 participants |
| Region of Enrollment Haiti | 69 participants | 71 participants | 140 participants |
| Region of Enrollment India | 246 participants | 258 participants | 504 participants |
| Region of Enrollment Peru | 75 participants | 73 participants | 148 participants |
| Region of Enrollment South Africa | 282 participants | 288 participants | 570 participants |
| Region of Enrollment Spain | 106 participants | 107 participants | 213 participants |
| Region of Enrollment Thailand | 304 participants | 286 participants | 590 participants |
| Region of Enrollment Uganda | 96 participants | 85 participants | 181 participants |
| Region of Enrollment United States | 1897 participants | 1890 participants | 3787 participants |
| Region of Enrollment Zimbabwe | 62 participants | 63 participants | 125 participants |
| Sex: Female, Male Female | 1211 Participants | 1208 Participants | 2419 Participants |
| Sex: Female, Male Male | 2677 Participants | 2673 Participants | 5350 Participants |
| Sex/Gender, Customized Cisgender | 3691 Participants | 3683 Participants | 7374 Participants |
| Sex/Gender, Customized Not reported | 134 Participants | 134 Participants | 268 Participants |
| Sex/Gender, Customized Transgender | 63 Participants | 64 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 126 / 3,888 | 143 / 3,881 |
| other Total, other adverse events | 488 / 3,888 | 420 / 3,881 |
| serious Total, serious adverse events | 750 / 3,888 | 755 / 3,881 |
Outcome results
Primary
Incidence Rate of Major Adverse Cardiovascular Event (MACE)
MACE is a composite of cardiovascular (CV) death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack (TIA), peripheral arterial ischemia, coronary, carotid or peripheral arterial revascularization, or death from an undetermined cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Major Adverse Cardiovascular Event (MACE) | 4.95 events per 1000 person-years |
| Placebo | Incidence Rate of Major Adverse Cardiovascular Event (MACE) | 7.77 events per 1000 person-years |
95% CI: [0.48, 0.84]
Secondary
Fasting Low-density Lipoprotein Cholesterol (LDL-C)
LDL-C level was derived as LDL-C calculated according to the Friedewald formula at triglycerides ≤400 mg/dL, and direct LDL-C at triglycerides \>400 to \<500 mg/dL. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.
Population: All participants enrolled according to the randomized treatment group. The number of participants with fasting LDL-C available is shown at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Entry: LDL-C | 107 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 12: LDL-C | 74 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 24: LDL-C | 75 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 36: LDL-C | 73 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 48: LDL-C | 73 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 60: LDL-C | 73 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 72: LDL-C | 74 mg/dL |
| Pitavastatin | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 84: LDL-C | 75 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 84: LDL-C | 98 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Entry: LDL-C | 106 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 48: LDL-C | 103 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 12: LDL-C | 105 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 72: LDL-C | 101 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 24: LDL-C | 104 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 60: LDL-C | 103 mg/dL |
| Placebo | Fasting Low-density Lipoprotein Cholesterol (LDL-C) | Month 36: LDL-C | 104 mg/dL |
Secondary
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C)
Non-HDL cholesterol levels were calculated as total cholesterol minus HDL cholesterol. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.
Population: All participants enrolled according to the randomized treatment group. The number of participants with fasting non-HDL-C available is shown at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 12: non-HDL-C | 97 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Entry: non-HDL-C | 133 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 24: non-HDL-C | 98 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 36: non-HDL-C | 97 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 48: non-HDL-C | 96 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 60: non-HDL-C | 96 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 72: non-HDL-C | 95 mg/dL |
| Pitavastatin | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 84: non-HDL-C | 99 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 84: non-HDL-C | 123 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 48: non-HDL-C | 128 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Entry: non-HDL-C | 132 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 12: non-HDL-C | 131 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 72: non-HDL-C | 124 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 24: non-HDL-C | 131 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 60: non-HDL-C | 127 mg/dL |
| Placebo | Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Month 36: non-HDL-C | 130 mg/dL |
Secondary
For Mechanistic Substudy: Change in HsCRP From Baseline
Change in inflammatory biomarker hsCRP from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Change in HsCRP From Baseline | -0.01 mg/mL |
| Placebo | For Mechanistic Substudy: Change in HsCRP From Baseline | 0.01 mg/mL |
Comparison: Comparison of Change in hsCRP from Baseline at Month 24p-value: 0.09Wilcoxon (Mann-Whitney)
Secondary
For Mechanistic Substudy: Change in LpPLA2 From Baseline
Change in inflammatory biomarker LpPLA2 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Change in LpPLA2 From Baseline | -9.77 ng/mL |
| Placebo | For Mechanistic Substudy: Change in LpPLA2 From Baseline | 19.9 ng/mL |
Comparison: Comparison of Change in LpPla2 from Baseline at Month 24p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2
NCP was defined as plaque voxels with attenuation of \<350. Change in NCP is expressed as absolute change from baseline (calculated as NCP volume at 2 years minus NCP volume at entry), based on quantitative read of the CT scan, whenever available. Participants without a quantitative read and no evidence of NCP based on the corresponding qualitative read were assigned a value of zero for the change. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and Year 2.
Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2 | -1.70 mm^3 | Standard Deviation 25.2 |
| Placebo | For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2 | 2.62 mm^3 | Standard Deviation 27.1 |
p-value: 0.0495% CI: [-8.6, -0.1]Regression, Linear
Secondary
For Mechanistic Substudy: Change in Soluble CD163 From Baseline
Change in immune biomarker soluble CD163 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Change in Soluble CD163 From Baseline | 149 ng/mL |
| Placebo | For Mechanistic Substudy: Change in Soluble CD163 From Baseline | 143 ng/mL |
Comparison: Comparison of Change in soluble CD163 from Baseline at Month 24p-value: 0.88Wilcoxon (Mann-Whitney)
Secondary
For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2
Total plaque includes all plaque voxels (noncalcified + calcified). Change in total plaque volume is expressed as absolute change from baseline (calculated as volume at 2 years minus volume at entry). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and year 2.
Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2 | 2.34 mm^3 | Standard Deviation 28.7 |
| Placebo | For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2 | 6.89 mm^3 | Standard Deviation 32.3 |
95% CI: [-9.2, 0.62]
Secondary
For Mechanistic Substudy: HsCRP Level
Level of inflammatory marker high-sensitivity C-reactive protein (HsCRP). Censored values below or above the assay limit were imputed. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pitavastatin | For Mechanistic Substudy: HsCRP Level | Entry | 0.18 mg/dL |
| Pitavastatin | For Mechanistic Substudy: HsCRP Level | Month 24 | 0.17 mg/dL |
| Placebo | For Mechanistic Substudy: HsCRP Level | Entry | 0.18 mg/dL |
| Placebo | For Mechanistic Substudy: HsCRP Level | Month 24 | 0.19 mg/dL |
Comparison: Comparison of hsCRP Levels at Month 24p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
For Mechanistic Substudy: LpPLA2 Level
Level of inflammatory biomarker lipoprotein-associated phospholipase A2 (LpPLA2). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pitavastatin | For Mechanistic Substudy: LpPLA2 Level | Entry | 126 ng/mL |
| Pitavastatin | For Mechanistic Substudy: LpPLA2 Level | Month 24 | 119 ng/mL |
| Placebo | For Mechanistic Substudy: LpPLA2 Level | Month 24 | 143 ng/mL |
| Placebo | For Mechanistic Substudy: LpPLA2 Level | Entry | 131 ng/mL |
Comparison: Comparison of LpPla2 Levels at Month 24p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2
Progression at Year 2 was defined as any progression/increase in NCP volume in participants with evidence of NCP at entry, or incident NCP in participants without evidence of NCP at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and year 2.
Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2 | 53 Participants |
| Placebo | For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2 | 85 Participants |
p-value: 0.00395% CI: [0.52, 0.88]Chi-squared
Secondary
For Mechanistic Substudy: Soluble CD163 Level
Level of immune biomarker soluble CD163. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: Entry and month 24.
Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pitavastatin | For Mechanistic Substudy: Soluble CD163 Level | Month 24 | 1013 ng/mL |
| Pitavastatin | For Mechanistic Substudy: Soluble CD163 Level | Entry | 849 ng/mL |
| Placebo | For Mechanistic Substudy: Soluble CD163 Level | Month 24 | 1003 ng/mL |
| Placebo | For Mechanistic Substudy: Soluble CD163 Level | Entry | 845 ng/mL |
Comparison: Comparison of soluble CD163 Levels at Month 24.p-value: 0.65Wilcoxon (Mann-Whitney)
Secondary
Incidence Rate of Adverse Event (AE)
Safety analysis outcome measure of any AE. AE collection included events of grade ≥3, those that were serious (defined by International Conference on Harmonisation (ICH) criteria) or treatment-limiting, and targeted diagnosis of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Adverse Event (AE) | 8.83 events per 100 person-years |
| Placebo | Incidence Rate of Adverse Event (AE) | 8.49 events per 100 person-years |
95% CI: [0.97, 1.12]
Secondary
Incidence Rate of AIDS-defining Event
AIDS-defining event component of the composite non-CV clinical diagnoses outcome. Events were captured based on the Centers for Disease Control and Prevention \[CDC\] 2014 classification. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of AIDS-defining Event | 3.36 events per 1000 person-years |
| Placebo | Incidence Rate of AIDS-defining Event | 3.55 events per 1000 person-years |
95% CI: [0.68, 1.31]
Secondary
Incidence Rate of Cardiac Catheterization or Revascularization
Cardiac cardiac catheterization or revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Cardiac Catheterization or Revascularization | 1.08 events per 1000 person-years |
| Placebo | Incidence Rate of Cardiac Catheterization or Revascularization | 1.77 events per 1000 person-years |
95% CI: [0.36, 1.05]
Secondary
Incidence Rate of Cardiac Ischemia or Myocardial Infarction
Cardiac ischemia or myocardial infarction component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Cardiac Ischemia or Myocardial Infarction | 1.48 events per 1000 person-years |
| Placebo | Incidence Rate of Cardiac Ischemia or Myocardial Infarction | 2.65 events per 1000 person-years |
95% CI: [0.36, 0.87]
Secondary
Incidence Rate of Carotid or Cerebrovascular Revascularization
Carotid or cerebrovascular revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Carotid or Cerebrovascular Revascularization | 0 events per 1000 person-years |
| Placebo | Incidence Rate of Carotid or Cerebrovascular Revascularization | 0 events per 1000 person-years |
Secondary
Incidence Rate of Cerebrovascular Event (Stroke or TIA)
Cerebrovascular event (stroke or TIA) component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Cerebrovascular Event (Stroke or TIA) | 1.53 events per 1000 person-years |
| Placebo | Incidence Rate of Cerebrovascular Event (Stroke or TIA) | 2.46 events per 1000 person-years |
95% CI: [0.4, 0.97]
Secondary
Incidence Rate of COVID-19
COVID-19 was defined as COVID-19 clinical diagnosis or positive test result (SARS-CoV-2 PCR or rapid antigen tests). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios (prescribed pitavastatin compared to placebo) from Poisson regression models, adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From January 1, 2020 through end of study; the median follow-up time was 3.3 years.
Population: Participants who remained in REPRIEVE follow-up at the start of the COVID-19 pandemic (defined as January 1, 2020), according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of COVID-19 | 8.79 events per 100 person-years |
| Placebo | Incidence Rate of COVID-19 | 8.35 events per 100 person-years |
95% CI: [0.96, 1.16]
Secondary
Incidence Rate of Death (All-cause)
Death from any cause. The incidence rates were estimated based on time to event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Death (All-cause) | 6.18 events per 1000 person-years |
| Placebo | Incidence Rate of Death (All-cause) | 6.99 events per 1000 person-years |
95% CI: [0.7, 1.12]
Secondary
Incidence Rate of Death From CV Causes
CV death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths and deaths from undetermined causes were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Death From CV Causes | 0.69 events per 1000 person-years |
| Placebo | Incidence Rate of Death From CV Causes | 0.98 events per 1000 person-years |
95% CI: [0.35, 1.38]
Secondary
Incidence Rate of Death From CV or Undetermined Causes
CV or undetermined death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Death From CV or Undetermined Causes | 1.72 events per 1000 person-years |
| Placebo | Incidence Rate of Death From CV or Undetermined Causes | 2.54 events per 1000 person-years |
95% CI: [0.44, 1.03]
Secondary
Incidence Rate of Diabetes
Safety analysis outcome measure of diabetes was defined as new diagnosis of diabetes with initiation of anti-diabetic agent. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: Participants without pre-existing diabetes at baseline, according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Diabetes | 1.18 events per 100 person-years |
| Placebo | Incidence Rate of Diabetes | 0.91 events per 100 person-years |
95% CI: [1.07, 1.57]
Secondary
Incidence Rate of End-Stage Liver Disease
End-stage liver disease (defined as cirrhosis or hepatic decompensation requiring hospitalization) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of End-Stage Liver Disease | 0.59 events per 1000 person-years |
| Placebo | Incidence Rate of End-Stage Liver Disease | 0.64 events per 1000 person-years |
95% CI: [0.42, 2.02]
Secondary
Incidence Rate of End-Stage Renal Disease
End-stage renal disease (defined as initiation of dialysis or renal transplantation) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of End-Stage Renal Disease | 0.15 events per 1000 person-years |
| Placebo | Incidence Rate of End-Stage Renal Disease | 0.24 events per 1000 person-years |
95% CI: [0.14, 2.51]
Secondary
Incidence Rate of Grade 3 or Higher ALT
Safety analysis outcome measure of Grade 3 or higher alanine transaminase (ALT). Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Grade 3 or Higher ALT | 0.059 events per 100 person-years |
| Placebo | Incidence Rate of Grade 3 or Higher ALT | 0.044 events per 100 person-years |
95% CI: [0.56, 3.18]
Secondary
Incidence Rate of MACE or Death
A composite outcome including MACE and death from any cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of MACE or Death | 9.31 events per 1000 person-years |
| Placebo | Incidence Rate of MACE or Death | 12.02 events per 1000 person-years |
95% CI: [0.64, 0.94]
Secondary
Incidence Rate of Myalgia, Muscle Weakness or Myopathy
Safety analysis outcome measure of myalgia, muscle weakness or myopathy which were grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Myalgia, Muscle Weakness or Myopathy | 0.46 events per 100 person-years |
| Placebo | Incidence Rate of Myalgia, Muscle Weakness or Myopathy | 0.29 events per 100 person-years |
95% CI: [1.14, 2.19]
Secondary
Incidence Rate of Non-AIDS-defining Cancer
Non-AIDS-defining cancer (excluding basal cell and squamous cell carcinomas of the skin) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Non-AIDS-defining Cancer | 5.25 events per 1000 person-years |
| Placebo | Incidence Rate of Non-AIDS-defining Cancer | 5.68 events per 1000 person-years |
95% CI: [0.71, 1.2]
Secondary
Incidence Rate of Non-CV Clinical Diagnoses
A composite of non-CV clinical diagnoses including: non-AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of the skin), AIDS-defining events (based on Centers for Disease Control and Prevention \[CDC\] 2014 classification), end-stage renal disease, and end-stage liver disease. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Non-CV Clinical Diagnoses | 9.17 events per 1000 person-years |
| Placebo | Incidence Rate of Non-CV Clinical Diagnoses | 9.90 events per 1000 person-years |
95% CI: [0.76, 1.13]
Secondary
Incidence Rate of Non-fatal Serious Adverse Event
Safety analysis outcome measure of non-fatal serious adverse event was defined by International Conference on Harmonisation (ICH) criteria. Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Non-fatal Serious Adverse Event | 4.17 events per 100 person-years |
| Placebo | Incidence Rate of Non-fatal Serious Adverse Event | 4.18 events per 100 person-years |
95% CI: [0.9, 1.1]
Secondary
Incidence Rate of Peripheral Arterial Ischemia
Peripheral arterial ischemia component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Peripheral Arterial Ischemia | 0.10 events per 1000 person-years |
| Placebo | Incidence Rate of Peripheral Arterial Ischemia | 0.15 events per 1000 person-years |
95% CI: [0.11, 4.02]
Secondary
Incidence Rate of Peripheral Arterial Revascularization
Peripheral arterial revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Peripheral Arterial Revascularization | 0 events per 1000 person-years |
| Placebo | Incidence Rate of Peripheral Arterial Revascularization | 0.29 events per 1000 person-years |
95% CI: [0, 0.54]
Secondary
Incidence Rate of Rhabdomyolysis
Safety analysis outcome measure of rhabdomyolysis which was grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Rhabdomyolysis | 0.015 events per 100 person-years |
| Placebo | Incidence Rate of Rhabdomyolysis | 0.020 events per 100 person-years |
95% CI: [0.17, 3.37]
Secondary
Incidence Rate of Serious COVID-19
Serious COVID-19 was defined as COVID-19 that resulted in hospitalization or death or was life-threatening as per the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline E2A definition. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
Time frame: From January 1, 2020 through end of study; the median follow-up time was 3.3 years.
Population: Participants who remained in REPRIEVE follow-up at the start of the COVID-19 pandemic (defined as January 1, 2020), according to the randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pitavastatin | Incidence Rate of Serious COVID-19 | 0.45 events per 100 person-years |
| Placebo | Incidence Rate of Serious COVID-19 | 0.60 events per 100 person-years |
95% CI: [0.52, 1.08]
Other Pre-specified
Incidence Rate of MACE by Race
Subgroup analysis of the primary composite MACE outcome measure (as described above) by race. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include race and interaction of race and treatment, to evaluate modification of statin effect.
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pitavastatin | Incidence Rate of MACE by Race | Among Asians | 1.6 events per 1000 person-years |
| Pitavastatin | Incidence Rate of MACE by Race | Among Blacks | 5.8 events per 1000 person-years |
| Pitavastatin | Incidence Rate of MACE by Race | Among Whites | 5.6 events per 1000 person-years |
| Pitavastatin | Incidence Rate of MACE by Race | Among Other | 5.0 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Race | Among Other | 5.7 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Race | Among Asians | 7.0 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Race | Among Whites | 7.5 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Race | Among Blacks | 8.7 events per 1000 person-years |
Comparison: Evaluation of treatment effect modification by race (i.e. pitavastatin effect differing between races).p-value: 0.14Regression, Cox
Comparison: Pitavastatin effect among Asians from subgroup analysis by race.95% CI: [0.09, 0.59]
Comparison: Pitavastatin effect among Blacks from subgroup analysis by race.95% CI: [0.46, 0.96]
Comparison: Pitavastatin effect among Whites from subgroup analysis by race.95% CI: [0.49, 1.13]
Comparison: Pitavastatin effect among Other race from subgroup analysis by race.95% CI: [0.36, 2.1]
Other Pre-specified
Incidence Rate of MACE by Sex
Subgroup analysis of the primary composite MACE outcome measure (as described above) by sex. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include sex and interaction of sex and treatment, to evaluate modification of statin effect.
Time frame: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
Population: All participants enrolled according to the randomized treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pitavastatin | Incidence Rate of MACE by Sex | Among females | 3.9 events per 1000 person-years |
| Pitavastatin | Incidence Rate of MACE by Sex | Among males | 5.5 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Sex | Among females | 6.2 events per 1000 person-years |
| Placebo | Incidence Rate of MACE by Sex | Among males | 8.5 events per 1000 person-years |
Comparison: Evaluation of treatment effect modification by sex (i.e. pitavastatin effect differing in females compared to males).p-value: 0.98Regression, Cox
Comparison: Evaluation of pitavastatin effect among females.95% CI: [0.39, 1.04]
Comparison: Evaluation of pitavastatin effect among males.95% CI: [0.48, 0.86]