Cardiovascular Risk and Health Among People With Human Immunodeficiency Virus (HIV) Eligible for Primary Prevention: Insights From the REPRIEVE Trial.

BACKGROUND: In addition to traditional cardiovascular (CV) risk factors, antiretroviral therapy, lifestyle, and human immunodeficiency virus (HIV)-related factors may contribute to future CV events in persons with HIV (PWH). METHODS: Among participants in the global REPRIEVE randomized trial, we characterized demographics and HIV characteristics relative to ACC/AHA pooled cohort equations (PCE) for atherosclerotic CV disease predicted risk and CV health evaluated by Life's Simple 7 (LS7; includes smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose). RESULTS: Among 7382 REPRIEVE participants (31% women, 45% Black), the median PCE risk score was 4.5% (lower and upper quartiles Q1, Q3: 2.2, 7.2); 29% had a PCE score <2.5%, and 9% scored above 10%. PCE score was related closely to known CV risk factors and modestly (<1% difference in risk score) to immune function and HIV parameters. The median LS7 score was 9 (Q1, Q3: 7, 10) of a possible 14. Only 24 participants (0.3%) had 7/7 ideal components, and 36% had ≤2 ideal components; 90% had <5 ideal components. The distribution of LS7 did not vary by age or natal sex, although ideal health was more common in low sociodemographic index countries and among Asians. Poor dietary and physical activity patterns on LS7 were seen across all PCE scores, including the lowest risk categories. CONCLUSIONS: Poor CV health by LS7 was common among REPRIEVE participants, regardless of PCE. This suggests a critical and independent role for lifestyle interventions in conjunction with conventional treatment to improve CV outcomes in PWH. Clinical Trials Registration: NCT02344290. AIDS Clinical Trials Group study number: A5332.

Patterns of Antiretroviral Therapy Use and Immunologic Profiles at Enrollment in the REPRIEVE Trial.

BACKGROUND: Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described. METHODS: The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics. RESULTS: A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status. CONCLUSIONS: There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02344290.

Pitavastatin versus pravastatin in adults with HIV-1 infection and dyslipidaemia (INTREPID): 12 week and 52 week results of a phase 4, multicentre, randomised, double-blind, superiority trial.

BACKGROUND: People living with HIV-1 infection are at greater risk for cardiovascular disease than seronegative adults. Treatment of dyslipidaemia with statins has been challenging in people with HIV because of an increased potential for drug interactions due to competing cytochrome P450 metabolism between statins and commonly used antiretroviral agents. Neither pitavastatin nor pravastatin depend on cytochrome P450 for primary metabolism. We aimed to assess the safety and efficacy of pitavastatin versus pravastatin in adults with HIV and dyslipidaemia. METHODS: In the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) randomised, double-blind, active-controlled, phase 4 trial (INTREPID, we recruited adults aged 18-70 years with controlled HIV (with CD4 counts >200 cells per µL and HIV-1 RNA <200 copies per mL) on antiretroviral therapy for at least 6 months and dyslipidaemia (LDL cholesterol 3·4-5·7 mmol/L and triglycerides ≤4·5 mmol/L) from 45 sites in the USA and Puerto Rico. Patients being treated with darunavir, or who had homozygous familial hypercholesterolaemia or any condition causing secondary dyslipidaemia, or a history of statin intolerance, diabetes, or coronary artery disease were not eligible. We randomly assigned patients (1:1) to pitavastatin 4 mg or pravastatin 40 mg with matching placebos once daily orally for 12 weeks, followed by a 40 week safety extension. Randomisation was stratified by viral hepatitis B or C coinfection and computer-generated. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was percentage change in fasting serum LDL cholesterol from baseline to week 12 and the primary efficacy analysis was done in the modified intention-to-treat population. The safety analysis included all patients who took at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT01301066. FINDINGS: Between Feb 23, 2011, and March 29, 2013, we randomly assigned 252 patients to the pitavastatin (n=126) or pravastatin group (n=126). LDL cholesterol reduction was 31·1% with pitavastatin and 20·9% with pravastatin (least squares mean difference -9·8%, 95% CI -13·8 to -5·9; p<0·0001) at 12 weeks. At week 52, four patients (3%) in the pitavastatin group and six (5%) in the pravastatin group had virological failure, with no significant difference between treatments. Both treatments had neutral effects on glucose metabolism parameters. 85 patients treated with pitavastatin (68%) and 88 patients treated with pravastatin (70%) reported treatment-emergent adverse events, and these caused study discontinuation in six patients (5%) versus five patients (4%). No serious adverse event occurred in more than one participant and none were treatment-related according to investigator assessment. The most common treatment-emergent adverse events were diarrhoea in the pitavastatin group (n=12, 10%) and upper respiratory tract infection in the pravastatin group (n=14, 11%). 11 treatment-emergent serious adverse events were noted in seven patients (6%) in the pitavastatin group (atrial septal defect, chronic obstructive pulmonary disease, chest pain, diverticulitis, enterovesical fistula, gastroenteritis, viral gastroenteritis, herpes dermatitis, multiple fractures, respiratory failure, and transient ischaemic attack) and four events in three patients (2%) in the pravastatin group (cerebrovascular accident, arteriosclerosis coronary artery, myocardial infraction, and muscle haemorrhage). In the pravastatin treatment group, one additional patient discontinued due to an adverse event (prostate cancer that was diagnosed during the screening period, 42 days before first dose of study treatment, and therefore was not a treatment-emergent adverse event). INTERPRETATION: The INTREPID results support guideline recommendations for pitavastatin as a preferred drug in the treatment of dyslipidaemia in people with HIV. FUNDING: Kowa Pharmaceuticals America and Eli Lilly and Company.