Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: implications for clinical management: the CREATE 1 study.

AIMS: The aim of this study is to determine the cardiovascular disease (CVD) risk profile of a large UK HIV cohort and how highly active antiretroviral therapy (HAART) affects this. METHODS: It is a cross-sectional study within a large inner city hospital and neighbouring district hospital. A total of 1021 HIV positive outpatients representative of the complete cohort and 990 who had no previous CVD were included in CVD risk analysis. We recorded demographics, HAART history and CVD risk factors. CVD and coronary heart disease (CHD) risks were calculated using the Framingham (1991) algorithm adjusted for family history. RESULTS: The non-CVD cohort (n = 990) was 74% men, 51% Caucasian and 73.1% were on HAART. Mean age was 41 +/- 9 years, systolic blood pressure 120 +/- 14 mmHg, total cholesterol 4.70 +/- 1.05 mmol/l, high-density lipoprotein-C 1.32 +/- 0.48 mmol/l and 37% smoked. Median CVD risk was 4 (0-56) % in men and 1.4 (0-37) % in women; CHD risks were 3.5 (0-36) % and 0.6 (0-16) %. CVD risk was > 20% in 6% of men and 1% of women and > 10% in 12% of men and 4% of women. CVD risk was higher in Caucasians than other ethnicities; the risk factor contributing most was raised cholesterol. For patients on their first HAART, increased CHD risk (26.2% vs. 6.5%; odds ratio 4.03, p < 0.001) was strongly related to the duration of therapy. CONCLUSIONS: Modifiable risk factors, especially cholesterol, and also duration of HAART, were key determinants of CVD risk. DISCUSSION: Regular CHD and/or CVD risk assessment should be performed on patients with HIV, especially during HAART therapy. The effect of different HAART regimens on CHD risk should be considered when selecting therapy.

Atorvastatin therapy is associated with improvement of oxidized low-density lipoprotein cholesterol levels, which correlates with the degree of stenosis in patients with carotid atheromatosis with and without prior angioplasty.

AIM: Oxidized low-density lipoprotein (oxLDL) is a pivotal factor of the atheromatous process. Statins reduce atheromatosis and cardiovascular risk. The aim of the present study was to investigate the effect of statin therapy on circulating oxLDL and the possible impact of such effect on stenosis due to carotid artery atheromatosis. METHODS: A total of 100 patients (76 males, median age 68 years) with carotid atheromatosis were enrolled. Those with stenosis >70% (n=50) were pre-treated with carotid angioplasty, whereas those with <70% were treated conservatively. Both groups were given low-dose atrorvastatin, tittered to maintain LDL cholesterol <100 mg/dL. Anthropometrics, complete lipid profile, and oxLDL were obtained in 1, 3, 6 and 12 months. Stenosis was evaluated by ultrasonography at baseline and 12 months. RESULTS: Lipid profile significantly improved at 12 months and oxLDL fell from 62.26+/-22.03 mg/dL at baseline to 44.49+/-21.75 mg/dL at 12 months (P<0.001). In the invasively pretreated group no restenosis was noticed; in the conservatively treated group a significant reduction of stenosis was demonstrated (47.6+/-13.2% vs 37.7+/-15.7%, P<0.001). The decrease of oxLDL correlated with the reduction of stenosis (r=0.17, P=0.018). In multivariate analysis, oxLDL was an independent risk factor for re-stenosis (hazard ratio=4.319, P<0.001). CONCLUSION: A marked reduction of oxLDL was shown in patients with carotid atheromatosis treated with low-dose atorvastatin. Moreover, oxLDL could be a measure of the degree of stenosis in such patients.

Impact of the metabolic syndrome and its components combinations on arterial stiffness in Type 2 diabetic men.

AIM: Arterial stiffness (AS) is a risk marker of atherosclerosis and coronary artery disease, yet its association with metabolic syndrome (MS) in diabetic patients is not established. The aim of this study was to investigate possible association of MS or its components with AS in diabetic population and to identify the MS definition which better correlates with AS. METHODS: Overall, 98 type-2 diabetic men, mean age 64+/-10 years, were classified into groups according to the presence of MS, using the National Cholesterol Educational Program-Adult Treatment Panel III (NCEP-ATPIII) and International Diabetes Federation (IDF) definition. AS was estimated using carotid-femoral pulse wave velocity (PWV). For between-group comparisons and correlations between MS and it's components with AS, t-test and Pearson's correlation coefficient were employed, respectively. For multivariable analysis a linear regression model was used. RESULTS: PWV in those with (72.5%) and without NCEP-ATPIII MS was 13.4+/-2.9 vs 12+/-3.2 m/s (P=NS) and in those with (79.6%) and without IDF MS 13.6+/-2.8 vs 11+/-3.2 m/s (P=0.036). AS positively correlated with IDF MS (r=0.332, P=0.036), increased blood pressure (r=0.324, P=0.037), and the combination of increased waist circumference according to IDF with hypertension (r=0.380, P=0.013); no correlation with NCEP-ATPIII MS was detected. In multivariable analysis, age, hypertension, and IDF MS were independently associated with AS (beta=2.52, P=0.039). CONCLUSIONS: IDF MS is independently associated with increased AS in diabetic men. Additionally, abdominal obesity, hypertension and older age were likely to be associated with increased AS. PWV measurement may be indicated in such patients.

Early detection of subclinical HIV sensory polyneuropathy using intraepidermal nerve fibre density quantification: association with HIV stage and surrogate markers.

The linear intraepidermal nerve fibre density (IENFD) and secondary branching were evaluated from skin biopsy of both the distal calf and the proximal thigh after staining with protein gene product 9.5 in 94 individuals of an HIV outpatient cohort. Possible correlations with clinical and electrophysiological evidence of distal sensory polyneuropathy (DSP), patients' demographics, antiretroviral history and HIV surrogate markers were analysed. Reduced IENFD was recognized in the majority of this population (mean +/- standard deviation [SD] IENFD in the calf and the thigh was 3.19 +/- 1.91 and 7.07 +/- 3.5 fibres/mm, respectively). One-third of the patients with low IENFD had no clinical or electrophysiological evidence of DSP. The level of prior immunosuppression as expressed by lower nadir CD4 count, more advanced HIV stage and prior exposure to combinations of neurotoxic antiretrovirals was associated with more decreased IENFD. Increased SB was associated with symptomatic DSP.

Distal sensory polyneuropathy in HIV-positive patients in the HAART era: an entity underestimated by clinical examination.

The aim of this study was to determine the prevalence of distal sensory polyneuropathy (DSP) in our HIV-positive patients under highly active antiretroviral therapy (HAART) and to investigate correlations with clinical, laboratory and demographic factors. One hundred consecutive HIV-positive patients underwent clinical and electrophysiological evaluation for DSP. Correlations with HIV stage, CD4 count, nadir CD4 count, viral load (VL), disease duration, age, sex and type of antiretrovirals were examined. Thirty-six percent of the patients had DSP (13% clinical, 23% subclinical diagnosed by electrophysiology). The prevalence of DSP was affected in a statistically significant manner by the diagnosis of AIDS (P = 0.00033), age (P = 0.0102), nadir CD4 count (P = 0.0087) and exposure to two neurotoxic antiretrovirals (P = 0.0189). Advanced HIV stage, sex, time from diagnosis, current CD4 count and VL did not seem to affect the prevalence of DSP. Clinical examination plus electrophysiology reveals that DSP affects 36% of patients under HAART, although subclinical in 2/3 of cases. Age, severe prior immunosuppression and the combined use of zalcitabine (ddC), stavudine (d4T) and didanosine (ddI) are important risk factors.

Breast cancer following curative chemotherapy for non-Hodgkin's lymphoma and the effect of drug resistance proteins to the final outcome. A retrospective study.

PURPOSE: To investigate the overall survival (OS) of patients developing breast cancer (BC) after curative chemotherapy for non-Hodgkin's lymphoma (NHL) and to evaluate the possible effect on the patients' outcome of the expression of drug resistance-related proteins (P-glycoprotein-Pgp, multidrug resistance-associated protein-MRP, and multidrug resistance-related vault lung resistance protein-LRP) in BC issue. STUDY GROUP: 25 female patients (median age 60 years, range 37-70) who developed BC after chemotherapy for high/intermediate grade B-cell NHL, treated with CHOP and achieving complete remission (CR). This group was further subdivided in subgroups A and B, according to the time interval between NHL and BC development ( 24 months, respectively). A matched-pair group of de novo BC patients formed the control group. BC tissue was immuno-histochemically stained for Pgp, MRP and LRP. RESULTS: The median interval between NHL diagnosis and BC development was 26 months (range 9-49). In both groups 14 patients had tumor grade II; 16 were negative for steroid receptors; 17 overexpressed c-erbB-2; 14 were stage IIIA/B, and 11 stage IV. CMF or CNF (mitoxantrone instead of doxorubicin) were given for BC. Early progression was noticed in all study group patients for which second-line chemotherapy was instituted. There was a better response for stage IV patients in the control versus the study group (p=0.07). More prolonged OS was demonstrate for patients with stage III in the control group (median 51 months) and in subgroup B (median 47 months) than in subgroup A (median 16 months; p=0.00012), as well as for patients with advanced disease (p=0.0045). Development of BC < 24 months after NHL resulted in reduced OS (p=0.017). No difference was noticed in the expression of drug resistance proteins between the study and control group or between subgroups A and B. CONCLUSION: BC developing shortly after a CR to NHL is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of Pgp, MRP and LRP failed to demonstrate significant difference between the study and control group, although indications exist that drug resistance mechanisms might be part of the aggressive disease phenotype, contributing to the poor outcome.

5-fluorouracil cardiotoxicity is a rare, dose and schedule-dependent adverse event: a prospective study.

PURPOSE: Cardiotoxicity associated with 5-fluorouracil (5FU) administration is infrequently reported in the literature, albeit case reports of acute coronary syndromes have been published. In the present study, patients undergoing 5FU chemotherapy were tested for the development of cardiac-related symptoms during its administration. PATIENTS AND METHODS: Five hundred twenty-two patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion were subjected to electrocardiogram (ECG) and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion was interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >2-fold enzyme elevation were admitted into a coronary care unit for at least 72 hours. Cases with acute myocardial infarction had to discontinue 5FU treatment. RESULTS: Overall 20 (3.8%) patients developed symptoms and/or ECG abnormalities due to 5FU. Patients with continuous 5FU infusion had a trend for higher incidence of cardiotoxicity (13/205, 6.3%) than the remaining (7/317, 2.2%; p=0.067). More specifically, increased toxicity was encountered in patients with continuous 24 h 5FU+ leucovorin (LV) infusion for 5 days compared to patients with the same schedule without LV (p <0.027) and patients with short 5FU+LV administration as well (p=0.024). Seven out of the 20 patients suffered acute myocardial infarction, 6 developed only ischemia, while ECG findings consistent with coronary vasospasm were detected in 4 patients and conduction disturbances in 3 patients (one subsequently died). CONCLUSION: The present study indicates a toxic effect of 5FU on myocardium, which is largely schedule-dependent. High level of alert is required when using this drug, while its toxic effect on the coronary endothelium and myocardium merits further investigation.

Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer.

In the present study, we evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU. Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.

An unusual case of brucellar spondylitis involving both the cervical and lumbar spine.

We report an unusual case of brucellar spondylitis, involving both the cervical and lumbar spine. Diagnosis was established using magnetic resonance imaging (MRI). An initial plain radiograph of the lumbar spine, showing mild degenerative lesions, was misleading. Therefore, institution of a proper treatment was delayed.