Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.)

Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy. We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1–phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis. We observed one grade 2 dental abscess that required hospitalization for treatment with antibiotics. Other adverse events were grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed an improvement of vasculitis in 8 of 10 patients. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25^high, forkhead box P3 (FOXP3+) Tregs [E_max (maximum value)÷baseline value×100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators. The trial showed that low-dose interleukin-2 led to Treg recovery and was associated with clinical improvement in 8 of 10 patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.)

Research from JAMA — Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected Patients — A Randomized Controlled Trial — ContextTreatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)–infected patients is a growing concern. Most data on the virologic efficacy and safety of the combination of peginterferon alfa-2b and ribavirin in coinfected patients come from uncontrolled studies.ObjectiveTo study the safety and efficacy of peginterferon alfa-2b plus ribavirin vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients.Design and SettingsA multicenter, randomized, parallel-group, open-label trial. Patients were enrolled from February 2000 to February 2002 and followed up for 72 weeks.PatientsFour hundred twelve HIV-HCV coinfected patients with detectable serum HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 × 106/L, and stable plasma HIV-RNA.InterventionTreatment with ribavirin 400 mg twice a day, orally, plus either peginterferon alfa-2b (1.5 μg/kg subcutaneous injection once a week) or standard interferon alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48 weeks.Main Outcome MeasuresSustained virologic response, defined by undetectable serum HCV-RNA at week 72.ResultsMore patients had sustained virologic responses in the peginterferon group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6% for standard interferon, P = .006) but was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon vs 43% for standard interferon, P = .88). Together, a decline in HCV-RNA of less than 2 log10 from baseline and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures. Histologic activity diminished and fibrosis stabilized in virologic responders. The 2 regimens showed similar tolerability although dose modifications for clinical and biological events were more frequent with peginterferon. Eleven cases of pancreatitis or symptomatic hyperlactatemia were observed, all in patients receiving didanosine-containing antiretroviral regimens.ConclusionIn combination with ribavirin, treatment with peginterferon alfa-2b is more effective than standard interferon alfa-2b for HCV infection in HIV-infected patients.