The CCR5Delta32 allele slows disease progression of human immunodeficiency virus-1-infected children receiving antiretroviral treatment.

The role of the CCR5Delta32 allele in human immunodeficiency virus (HIV)-1-related disease progression was analyzed for 457 antiretroviral-naïve children who had participated in the Pediatric AIDS Clinical Trials Group 152 study, which demonstrated that didanosine (ddI) or zidovudine + ddI treatments were superior to zidovudine alone. The CCR5Delta32 allele was detected at an overall frequency of 6.1% (28/457). At study entry, heterozygote children (wild type [wt]/Delta32) had higher baseline median CD4(+) counts/mm(3) than wt/wt children had (1035 vs. 835 cells/mm(3); P=. 043), higher mean weight-for-age Z scores (-0.15 vs. -0.84; P=.01), and a trend toward less cortical atrophy (P=.059). During antiretroviral treatment and study follow-up, there was a trend toward less disease progression and death among heterozygote children than among wt/wt children (P=.056; relative hazard, 0.28; 95% confidence interval, 0.07-1.13) independent of the antiretroviral treatment to which they were randomized.

Predicting HIV disease progression in children using measures of neuropsychological and neurological functioning. Pediatric AIDS clinical trials 152 study team.

BACKGROUND: Neuropsychological testing and 2 measures of neurological status, cortical atrophy, and motor dysfunction were assessed for their usefulness in predicting human immunodeficiency virus (HIV) disease progression in infants, children, and adolescents who participated in Pediatric AIDS Clinical Trials Group Protocol 152 (PACTG 152). METHODS: A cohort of 722 antiretroviral therapy-naive children with symptomatic HIV infection were assessed at study entry and at later intervals. Assessments included neurodevelopmental testing, neuroradiologic imaging, and neurological examination of motor function. CD4 cell count and plasma RNA viral load also were measured. RESULTS: Children with the lowest neuropsychological functioning (IQ < 70) at baseline had the highest risk for later HIV disease progression (56%), compared with those with borderline/low (IQ = 70-89) functioning (26%), or with average or above (IQ > 90) functioning (18%). This was also true of week 48 neuropsychological functioning. Motor dysfunction (especially reduced muscle mass) at entry also predicted disease progression. Furthermore, motor dysfunction and week 48 neuropsychological functioning provided predictive information beyond that obtainable from surrogate markers of HIV disease status (eg, CD4 count, HIV RNA level). Children with cortical atrophy also were at higher risk for later disease progression, but when CD4 count and RNA viral load were known, cortical atrophy information provided no additional predictive information. CONCLUSIONS: Measures of neuropsychological and motor function status provide unique information regarding pediatric HIV disease progression. As such, these findings have important implications for predicting long-term outcomes (eg, longevity) in pediatric patients.

Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team.

OBJECTIVES: To compare the impact of three different nucleoside reverse transcriptase inhibitor regimens, zidovudine (ZDV) monotherapy, didanosine (ddI) monotherapy, and ZDV plus ddI combination therapy, on central nervous system (CNS) outcomes in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: Serial neurologic examinations, neurocognitive tests, and brain growth assessments (head circumference measurements and head computed tomography or magnetic resonance imaging studies) were performed in 831 infants and children who participated in a randomized double-blind clinical trial of nucleoside reverse transcriptase inhibitors. The Pediatric AIDS Clinical Trials Group study 152 conducted between 1991 and 1995 enrolled antiretroviral therapy-naive children. Subjects were stratified by age (3 to <30 months of age or 30 months to 18 years of age) and randomized in equal proportions to the three treatment groups. RESULTS: Combination ZDV and ddI therapy was superior to either ZDV or ddI monotherapy for most of the CNS outcomes evaluated. Treatment differences were observed within both age strata. ZDV monotherapy showed a modest statistically significant improvement in cognitive performance compared with ddI monotherapy during the initial 24 weeks, but for subsequent protection against CNS deterioration no clear difference was observed between the two monotherapy arms. CONCLUSIONS: Combination therapy with ZDV and ddI was more effective than either of the two monotherapies against CNS manifestations of human immunodeficiency virus disease. The results of this study did not indicate a long-term beneficial effect for ZDV monotherapy compared with ddI monotherapy.

Virologic and immunologic response to nucleoside reverse-transcriptase inhibitor therapy among human immunodeficiency virus-infected infants and children.

Plasma human immunodeficiency virus RNA and CD4 lymphocyte response to nucleoside reverse-transcriptase therapy were evaluated in a large, comparative pediatric trial. Both baseline values and changes in the two laboratory markers over time correlated well with clinical outcome and possessed independent predictive value. In comparison of RNA reduction from baseline between the dideoxyinosine (ddI) and zidovudine+ddI therapeutic arms, marginal superiority of the combination arm was not correlated with an observed clinical benefit. Despite the size of this trial and the significantly higher rate of clinical end points in the zidovudine monotherapy group, attempts to establish surrogacy for plasma RNA were difficult. Nevertheless, plasma RNA and CD4 lymphocyte count together possess strong clinical predictive power and are valuable tools for both the clinician and the evaluation of new therapies.

Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children.

CONTEXT: Pediatric human immunodeficiency virus (HIV) infection has unique viral pathogenetic features that preclude routine extrapolation from adult studies and require specific analysis. OBJECTIVES: To evaluate the prognostic value of 2 key laboratory markers-plasma RNA and CD4+ lymphocyte count-for HIV disease progression in infants and children and to establish targeted values for optimal outcome. DESIGN: Data from a cohort of 566 infants and children who participated in a randomized, placebo-controlled trial of nucleoside reverse transcriptase inhibitors (ACTG 152) were analyzed. The trial was conducted between 1991 and 1995 and enrolled a heterogeneous cohort of antiretroviral therapy-naive children (age, 3 months to 18 years); patients had a median follow-up of 32 months. MAIN OUTCOME MEASURES: The trial clinical end points consisted of time to first HIV disease progression (growth failure, decline in neurologic or neurodevelopmental function, opportunistic infections) or death. RESULTS: Baseline plasma RNA levels were high (age group medians, 5 x 10(4) to >10(6) copies/mL), and both baseline RNA and CD4+ lymphocyte count were independently predictive of subsequent clinical course. Risk reduction for disease progression between 49% and 64% was observed for each log10 reduction in baseline RNA and was linear without suggestion of a threshold or age effect. Disease progression predictive power was enhanced by the combined use of plasma RNA and CD4+ cell count. Marker values of less than 10000 copies/mL for plasma RNA and greater than 500 x 10(6)/L (<6.5 years of age) or greater than 200 x 10(6)/L (>6.5 years) for CD4+ cell count were associated with a 2-year disease progression rate of less than 5%. CONCLUSIONS: Two key laboratory markers--plasma RNA and CD4+ lymphocyte count-are independent predictors of clinical course among HIV-infected infants and children. The linear, age-independent relationship between log10 plasma RNA and relative risk of disease progression strongly supports therapeutic efforts to achieve plasma virus levels as low as possible.

Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team.

BACKGROUND: Zidovudine has been the drug of choice for the initial treatment of symptomatic children infected with the human immunodeficiency virus (HIV). This trial was designed to assess the efficacy and safety of treatment with zidovudine alone as compared with either didanosine alone or combination therapy with zidovudine plus didanosine. METHODS: In this multicenter, double-blind study, symptomatic HIV-infected children 3 months through 18 years of age were stratified according to age (<30 months or > or =30 months) and randomly assigned to receive zidovudine, didanosine, or zidovudine plus didanosine. The primary end point was length of time to death or to progression of HIV disease. RESULTS: Of the 831 children who could be evaluated, 92 percent had never received antiretroviral therapy and 90 percent had acquired HIV perinatally. An interim analysis (median follow-up, 23 months) showed a significantly higher risk of HIV-disease progression or death in patients receiving zidovudine alone than in those receiving combination therapy (relative risk, 0.61; 95 percent confidence interval, 0.42 to 0.88; P=0.007). The study arm with zidovudine alone was stopped and unblinded; the other two treatment arms were continued. At the end of the study, didanosine alone had an efficacy similar to that of zidovudine plus didanosine (median follow-up, 32 months) (relative risk of disease progression or death, 0.98; 95 percent confidence interval, 0.70 to 1.37; P=0.91). A significantly lower risk of anemia or neutropenia was seen in patients receiving didanosine alone (P=0.036). CONCLUSIONS: In symptomatic HIV-infected children, treatment with either didanosine alone or zidovudine plus didanosine was more effective than treatment with zidovudine alone. The efficacy of didanosine alone was similar to that of the combination therapy and was associated with less hematologic toxicity.

Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children. AIDS Clinical Trials Group Protocol 152 Study Team.

BACKGROUND: A large cohort of antiretroviral therapy-naive, symptomatic, HIV-infected children were enrolled into a controlled therapeutic trial (AIDS Clinical Trials Group Protocol 152), providing an opportunity to describe their clinical and laboratory characteristics and determine age-related distinctions. METHODS: Study entry evaluations for 838 of 839 enrolled children were analyzed. Weight, head circumference (if < 30 months of age), neuroradiologic imaging of the head, developmental or cognitive status and neurologic examination were assessed. Laboratory studies included hemoglobin, absolute neutrophil count, CD4 cell count, serum amylase, alanine aminotransaminase, p24 antigen and HIV blood culture. Data were categorized by age (3 to < 12 months, 12 to < 30 months, 30 months to 6 years and > or = 6 years). RESULTS: Younger children had significantly higher rates of abnormalities before antiretroviral therapy, especially factors relating to growth and neurologic or cognitive function. Lower CD4+ cell counts and percentages as well as a positive serum p24 antigen correlated with lower weight-for-age Z scores and developmental indices. CONCLUSIONS: These data provide a description of the clinical characteristics of HIV-infected US children at the time antiretroviral therapy is initiated for HIV-related symptoms. The high rate of abnormalities of growth, development and cognitive ability that were observed in children < 30 months of age demonstrates that treatment strategies should be developed for earlier intervention.

Variations in the use of coronary arteriography in the UK: the RITA trial coronary arteriogram register.

The Randomised Intervention Treatment of Angina (RITA) trial is comparing the effects of coronary artery bypass surgery and coronary angioplasty. During patient recruitment, the trial participants maintained a register of patients investigated by coronary arteriography. We used the register data to analyse variation in the practice and therapeutic implications of coronary arteriography between the 17 participating centres. Of 33,359 patients undergoing coronary arteriography, 85.2% had significant coronary artery disease (range 81.3%-89.3% between centres). The planned management for patients with coronary disease included coronary bypass surgery (43.3%), coronary angioplasty (15.7%) and RITA randomization (3.2%). The rate of referral for myocardial revascularization varied between centres from 47.6% to 83.4%. Multiple logistic regression analysis identified several correlates of myocardial revascularization, including the indication for investigation, extent of coronary disease and left ventricular function. After adjustment for these variables, the odds of revascularization at the different participating centres varied by a factor of 4.2. This intercentre variation in the use of revascularization procedures may reflect variation in the clinician's view of the appropriateness of myocardial revascularization in different clinical circumstances.

Prothrombin activation fragment 1 + 2 and thrombin antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis.

Plasma levels of the prothrombin activation fragment 1 + 2 (F 1 + 2) and of thrombin antithrombin III complexes (TAT) were determined in 225 patients with angina pectoris undergoing coronary angiography. Oral anticoagulant therapy was associated with a marked reduction in mean F1 + 2 (0.63 vs 1.62 nmol/l, p < 0.0001) and TAT levels (1.65 vs 2.23 micrograms/l, p < 0.0001). Omitting patients on oral anticoagulants, TAT values showed a positive association with patients' age (r = 0.18; p = 0.01) and were slightly higher in patients with a history of myocardial infarction than in those without (2.47 vs 2.11 micrograms/l; p = 0.06). Both F1 + 2 and TAT levels were increased in patients with angiographically verified coronary atherosclerosis as compared to patients with angina and angiographically normal coronaries (F1 + 2: 1.76 vs 1.36 nmol/l, TAT: 2.35 vs 2.00 micrograms/l; p-values after adjusting for age, sex and past history of myocardial infarction 0.06 and 0.11 respectively). However, no graded relationship between F1 + 2 or TAT values and severity of atherosclerosis was observed. This study provides suggestive evidence that a procoagulant state exists in patients with angina pectoris and coronary atherosclerosis. Its relevance in predicting coronary ischaemic events needs to be studied prospectively.

Factors affecting the precision of warfarin treatment.

AIM: To determine what factors influence the precision of anticoagulant control using warfarin by examining the computerised records of 2207 patients. METHODS: Records from seven district general hospitals were combined and analysed. The precision of anticoagulant control was taken as the absolute deviation of International Normalised Ratio (INR) from target at the most recent determination. This quantity was examined using univariate and multiple regression analyses. RESULTS: Deviation of INR from target was continuously distributed, almost symmetrically about a mean of zero. The patients' age and sex had little bearing on control. Patients with a high target INR were more likely to be undertreated, and patients taking higher doses of warfarin were more likely to be overtreated. Previous over- or undertreatment were strongly related to poorer current control. The control of treatment varied substantially among the seven hospitals. One possible cause of this variation was the dose adjustment coefficient: the greater the dose adjustment for a given deviation from target INR, the better was the control achieved. CONCLUSION: Several groups of patients were identified whose control was less satisfactory and in whom anticoagulant treatment needs particular scrutiny: these include patients with a record of previous over- or undertreatment, but not elderly patients in general. The variation in control among hospitals is a source of concern that merits further attention to achieve better uniformity of anticoagulant treatment.

Prediction of short-term survival with an application in primary biliary cirrhosis.

Many long-term follow-up studies for survival accumulate repeated measurements of prognostic factors. Survival models which include only covariate values at baseline do not use all available information, and do not relate to survival predictions for times other than at that baseline. Time-dependent covariate models (which update covariate values as measurements occur through time) might be used, though limitations of software for estimating the underlying hazard functions and difficulty in relating hazard function changes to survival prediction present serious drawbacks. By dividing each patient's follow-up into successive intervals of equal length (using a length of interest for prediction) and with measurements available at the start of each, we describe how an analysis taking person-intervals as the observation units can be undertaken using readily available software to produce short-term survival models. We show that this approach is related to both the baseline and time-dependent covariate models. The method is illustrated using data from a long-term study of patients with primary biliary cirrhosis, where interest is in short-term survival predictions to aid the decision when to undertake liver transplantation.

Factors affecting the maintenance dose of warfarin.

AIM: To identify the possible factors determining the dose of warfarin prescribed in patients receiving anticoagulant treatment. METHODS: The computerised records of 2305 patients maintained on the drug in seven hospitals were amalgamated and classified into one of seven diagnostic groups. The associations with the dose of warfarin prescribed were investigated by univariate and multiple regression analysis. Differences between hospitals were studied with regard to the coagulometric method and the thromboplastin preparation used. RESULTS: The geometric mean dose of warfarin was 4.57 mg and 5% of patients were prescribed 10 mg or greater. There was a noticeable decrease in dose with increasing age, which averaged about 6 mg for patients aged 30 but 3.5 mg for those aged 80. Men required slightly more warfarin than women. Patients with heart disease or atrial fibrillation required lower doses of warfarin, while higher doses were required by patients with deep vein thrombosis. Significant differences in mean warfarin dose among the seven hospitals were evident. These differences could not be explained entirely by the use of different coagulometric methods or thromboplastins. CONCLUSIONS: Clinicians should be aware that older patients need reduced doses of warfarin. The considerable differences in doses of warfarin among hospitals indicates that further efforts to improve uniformity are required.

Comparative long-term results of coronary angioplasty in single and multivessel disease.

The comparative long-term clinical results of coronary angioplasty in 448 patients with single-vessel and 451 patients with multivessel disease are reported. Clinical status was determined at census for 898 patients (99.9%). Actuarial survival at 5 years was 92.7% for single-vessel and 85.6% for multivessel disease patients (relative risk 2.1). Patients with multivessel disease had higher rates of cardiac death and non-fatal myocardial infarction (relative risk 1.8), and coronary artery bypass surgery (relative risk 2.5) than patients with single-vessel disease. At follow-up 72.6% of single-vessel and 61.3% of multivessel disease patients had no angina and 43.3% and 35.8%, respectively, were taking no regular anti-anginal medication. Treatment by coronary angioplasty is associated with a good long-term prognosis, but survival and event-free survival rates are lower in patients with multivessel disease than in patients with single-vessel disease, even after correction for differences in other baseline characteristics.