In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist ...over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.
Delayed access to medical care in patients with acute myocardial infarction (AMI) is common and increases myocardial damage and mortality.
To evaluate a community intervention to reduce patient delay ...from symptom onset to hospital presentation and increase emergency medical service (EMS) use.
The Rapid Early Action for Coronary Treatment Trial, a randomized trial conducted from 1995 to 1997 in 20 US cities (10 matched pairs; population range, 55,777-238,912) in 10 states.
A total of 59,944 adults aged 30 years or older presenting to hospital emergency departments (EDs) with chest pain, of whom 20,364 met the primary population criteria of suspected acute coronary heart disease on admission and were discharged with a coronary heart disease-related diagnosis.
One city in each pair was randomly assigned to an 18-month intervention that targeted mass media, community organizations, and professional, public, and patient education to increase appropriate patient actions for AMI symptoms (primary population, n=10,563). The other city in each pair was randomly assigned to reference status (primary population, n=9801).
Time from symptom onset to ED arrival and EMS use, compared between intervention and reference city pairs.
General population surveys provided evidence of increased public awareness and knowledge of program messages. Patient delay from symptom onset to hospital arrival at baseline (median, 140 minutes) was identical in the intervention and reference communities. Delay time decreased in intervention communities by -4.7% per year (95% confidence interval CI, -8.6% to -0.6%), but the change did not differ significantly from that observed in reference communities (-6. 8% per year; 95% CI, -14.5% to 1.6%; P=.54). EMS use by the primary study population increased significantly in intervention communities compared with reference communities, with a net effect of 20% (95% CI, 7%-34%; P<.005). Total numbers of ED presentations for chest pain and patients with chest pain discharged from the ED, as well as EMS use among patients with chest pain released from the ED, did not change significantly.
In this study, despite an 18-month intervention, time from symptom onset to hospital arrival for patients with chest pain did not change differentially between groups, although increased appropriate EMS use occurred in intervention communities. New strategies are needed if delay time from symptom onset to hospital presentation is to be decreased further in patients with suspected AMI. JAMA. 2000;284:60-67
Treatment of SIV-infected rhesus macaques with short-term antiretroviral therapy (ART) and partially overlapping infusions of antibody to integrin α
β
was reported to induce durable posttreatment ...viral suppression. In an attempt to replicate those observations, we treated macaques infected with the same virus and with the same ART and monoclonal antibody (mAb) regimens (anti-α
β
versus control mAb). Sequencing demonstrated that the virus used was actually SIVmac239-
, not wild-type SIVmac239. A positive correlation was found at 2 weeks after infection between the frequency of repair of attenuated
virus to pathogenic
and plasma SIV RNA levels. Levels of plasma viremia before the first antibody infusion and preinfection levels of α
β
CD4
T cells, but not treatment with antibody to α
β
, correlated with levels of viral replication upon discontinuation of all treatments. Follow-up plasma viremia, peripheral blood CD4
T cell counts, and lymph node and rectal tissue viral load were not significantly different between anti-α
β
and control mAb groups.
Effects of diet on blood lipids are best known in white men, and effects of type of carbohydrate on triacylglycerol concentrations are not well defined.
Our goal was to determine the effects of diet ...on plasma lipids, focusing on subgroups by sex, race, and baseline lipid concentrations.
This was a randomized controlled outpatient feeding trial conducted in 4 field centers. The subjects were 436 participants of the Dietary Approaches to Stop Hypertension (DASH) Trial mean age: 44.6 y; 60% African American; baseline total cholesterol: < or = 6.7 mmol/L (< or = 260 mg/dL). The intervention consisted of 8 wk of a control diet, a diet increased in fruit and vegetables, or a diet increased in fruit, vegetables, and low-fat dairy products and reduced in saturated fat, total fat, and cholesterol (DASH diet), during which time subjects remained weight stable. The main outcome measures were fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triacylglycerol.
Relative to the control diet, the DASH diet resulted in lower total (-0.35 mmol/L, or -13.7 mg/dL), LDL- (-0.28 mmol/L, or -10.7 mg/dL), and HDL- (-0.09 mmol/L, or -3.7 mg/dL) cholesterol concentrations (all P < 0.0001), without significant effects on triacylglycerol. The net reductions in total and LDL cholesterol in men were greater than those in women by 0.27 mmol/L, or 10.3 mg/dL (P = 0.052), and by 0.29 mmol/L, or 11.2 mg/dL (P < 0.02), respectively. Changes in lipids did not differ significantly by race or baseline lipid concentrations, except for HDL, which decreased more in participants with higher baseline HDL-cholesterol concentrations than in those with lower baseline HDL-cholesterol concentrations. The fruit and vegetable diet produced few significant lipid changes.
The DASH diet is likely to reduce coronary heart disease risk. The possible opposing effect on coronary heart disease risk of HDL reduction needs further study.
The gut mucosa is an important site of HIV immunopathogenesis with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling ...and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with beta 7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV-RNA. These data suggest that gut T-cell activation and microbial translocation may be interconnected whereas prolonged ART may decrease activation and restore gut CD4+ T cells.
The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of ...HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART).
We conducted two open-label trials (AIDS Clinical Trials Group ACTG A5340 and National Institutes of Health NIH 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART.
A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus.
VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).
To assess the reliability of electron beam computed tomography (CT) in the detection of calcific deposits in coronary arteries.
The authors quantitatively evaluated a total of 4,298 segments of ...coronary arteries with electron beam CT and histomorphometry.
Regression analysis of the electron beam CT calcium score versus histomorphometric calcium area produced an r2 value of .92 (r = .96; P < .0001). Ninety-three percent (78 of 84) of all coronary arteries with stenosis of 76%-100% contained calcific deposits, and 20% (17 of 83) of all coronary arteries with stenosis of 0%-50% contained calcific deposits.
The amount of calcific deposits detected with electron beam CT correlates highly with histomorphometric measurements. Also, the amount of calcific deposits correlates well with the degree of coronary artery stenosis. Electron beam CT, therefore, is a promising noninvasive technique that can help depict the presence and extent of atherosclerotic plaques.
We propose a flexible method of extending a study based on conditional power. The possibility for extension when the p value at the planned end is small but not statistically significant is built in ...to the design of the study. The significance of the treatment difference at the planned end is used to determine the number of additional observations needed and the critical value necessary for use after accruing those additional observations. It may therefore be thought of as a two-stage procedure. Even though the observed treatment difference at stage 1 is used to make decisions, the Type I error rate is protected.
Although group characteristics are known to influence average blood pressure response to changes in salt intake, predictability of individual responses is less clear. We examined variability and ...consistency of individual systolic blood pressure responses to changes in salt intake in 188 participants who ate the same diet at higher, medium, and lower (140, 104, 62 mmol/d) sodium levels for 30 days each, in random order, after 2 weeks of run-in at the higher sodium level. Regarding variability in systolic blood pressure changes over time, changes from run-in to higher sodium (no sodium level change) ranged from -24 to +25 mm Hg; 8.0% of participants decreased > or =10 mm Hg. Regarding variability in systolic blood pressure response to change in sodium intake, with higher versus lower sodium levels (78-mmol sodium difference), the range of systolic blood pressure change was -32 to +17 mm Hg; 33.5% decreased > or =10 mm Hg. Regarding consistency of response, systolic blood pressure change with run-in versus lower sodium was modestly correlated with systolic blood pressure change with higher versus medium sodium; systolic blood pressure change with higher versus lower sodium was similarly correlated with run-in versus medium sodium (combined Spearman r=0.27, P=0.002). These results show low-order consistency of response and confirm that identifying individuals as sodium responders is difficult. They support current recommendations for lower salt intake directed at the general public rather than "susceptible" individuals as one of several strategies to prevent and control adverse blood pressures widely prevalent in the adult population.
PDF
