Roger Darioli

Atherogenic Dyslipidemia in HIV-Infected Individuals Treated With Protease Inhibitors

BACKGROUND Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir. METHODS AND RESULTS Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir. CONCLUSIONS Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.

Premature atherosclerosis in HIV-infected individuals : focus on protease inhibitor therapy

ObjectiveLipid disorders associated with the use of protease inhibitors may contribute to the premature development of atherosclerosis. The purpose of the present study was to determine whether the administration of a protease inhibitor-containing regimen to middle-aged (30–50 years) HIV-infected individuals for 6 months or longer is associated with an increased prevalence of atherosclerosis. MethodsHigh-resolution B-mode ultrasound imaging was used to visualize the femoral and carotid arteries of 68 HIV-negative and 168 HIV-infected individuals, including 136 patients who had received protease inhibitors for 26.8 ± 8.9 months (mean ± SD). Atherogenic plaques were defined as a thickening of the intima–media ⩾ 1200 mm. ResultsThe proportion of participants with one or more plaques was higher in the HIV-infected group in comparison with the HIV-negative group (55 versus 38%;P = 0.02), and so was the prevalence of cigarette smoking (61 versus 46%;P = 0.03) and hyperlipidaemia (56 versus 24%;P < 0.001). The presence of plaque was independently associated with age, male gender, plasma low-density lipoprotein cholesterol levels and smoking. In univariate logistic regression analysis, an association was also found with HIV infection. Among HIV-infected subjects protease inhibitor therapy was not associated with the presence of plaque. ConclusionsA large proportion of the middle-aged HIV-infected individuals examined during this study had one or more atherosclerotic plaques within the femoral or carotid arteries. The presence of peripheral atherosclerosis within this population is not associated with the use of protease inhibitors, but rather with ‘classic’ cardiovascular risk factors such as smoking and hyperlipidaemia, which are amenable to interventions.

Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders

BACKGROUND Single-nucleotide polymorphisms in genes involved in lipoprotein and adipocyte metabolism may explain why dyslipidemia and lipoatrophy occur in some but not all antiretroviral therapy (ART)-treated individuals. METHODS We evaluated the contribution of APOC3 -482C-->T, -455T-->C, and 3238C-->G; epsilon 2 and epsilon 4 alleles of APOE; and TNF -238G-->A to dyslipidemia and lipoatrophy by longitudinally modeling >2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years. RESULTS In human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population. However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia. They had median plasma triglyceride levels of 7.33 mmol/L, compared with 3.08 mmol/L in the absence of ART. The net effect of the APOE*APOC3*ritonavir interaction was an increase in plasma triglyceride levels of 2.23 mmol/L. No association between TNF -238G-->A and lipoatrophy was observed. CONCLUSIONS Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV. Interactions between genotypes and ART can lead to severe hyperlipidemia. Genetic analysis may identify patients at high risk for severe ritonavir-associated hypertriglyceridemia.

Effects of repeated annual influenza vaccination on vaccine sero-response in young and elderly adults

Three cohort studies in adults were performed during the period from 1986 to 1989. Eight hundred and eighty-four subjects were, one or more times, immunized with influenza vaccines, and pre- and post-vaccination antibody titres were determined by hemagglutination inhibition tests. One thousand and one hundred and nineteen vaccination events in 681 subjects could be analysed by a comparison, per trial and per influenza (sub)type, between groups with and without influenza vaccination in previous years. Effect size, odds ratio and protection rate difference, were used as effect measures. Subjects with previous vaccination showed higher pre-vaccination antibody than those without. The average change of the post-vaccination proportion of subjects with high antibody titre value to previous vaccination, was +9.4% (95% CI: +5.3 to 13.6%) for A-H3N2 vaccine components, -2.1% (-8.1 to 3.9%, not significant) for A-H1N1 and -10.6% (-16.5% to -4.8%) for B. In a linear regression model, pre-vaccination titres and the status of previous vaccination were identified as factors significantly influencing post-vaccination titres. These findings are discussed in the context of a short review of the literature. It is concluded that the status of previous vaccination should always be addressed as an independent factor in serological vaccination studies.

Electronic Monitoring of Compliance to Lipid‐Lowering Therapy in Clinical Practice

Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6‐month course of lipid‐lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS™), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 × 40 mg daily, provided in a MEMS™ package to record the date and time of each opening of the pillbox. Thirty‐nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6‐month therapy period. A high mean rate of compliance was achieved by MEMS™ using the following three indexes—compliance to total prescribed dose (88.8% ± 13.5%), compliance to prescribed days (82.4% ± 19.5%), and compliance to prescribed time of day (81.86% ± 19.5%)—and by pill count (93.4% ± 9.5%). In addition, the MEMS™ provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS™. The results indicate that MEMS™ is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long‐term lipid‐lowering therapy.

Contribution of 20 single nucleotide polymorphisms of 13 genes to dyslipidemia associated with antiretroviral therapy

Background HIV-1 infected individuals have an increased cardiovascular risk which is partially mediated by dyslipidemia. Single nucleotide polymorphisms in multiple genes involved in lipid transport and metabolism are presumed to modulate the risk of dyslipidemia in response to antiretroviral therapy. Methods The contribution to dyslipidemia of 20 selected single nucleotide polymorphisms of 13 genes reported in the literature to be associated with plasma lipid levels (ABCA1, ADRB2, APOA5, APOC3, APOE, CETP, LIPC, LIPG, LPL, MDR1, MTP, SCARB1, and TNF) was assessed by longitudinally modeling more than 4400 plasma lipid determinations in 438 antiretroviral therapy-treated participants during a median period of 4.8 years. An exploratory genetic score was tested that takes into account the cumulative contribution of multiple gene variants to plasma lipids. Results Variants of ABCA1, APOA5, APOC3, APOE, and CETP contributed to plasma triglyceride levels, particularly in the setting of ritonavir-containing antiretroviral therapy. Variants of APOA5 and CETP contributed to high-density lipoprotein-cholesterol levels. Variants of CETP and LIPG contributed to non-high-density lipoprotein-cholesterol levels, a finding not reported previously. Sustained hypertriglyceridemia and low high-density lipoprotein-cholesterol during the study period was significantly associated with the genetic score. Conclusions Single nucleotide polymorphisms of ABCA1, APOA5, APOC3, APOE, and CETP contribute to plasma triglyceride and high-density lipoprotein-cholesterol levels during antiretroviral therapy exposure. Genetic profiling may contribute to the identification of patients at risk for antiretroviral therapy-related dyslipidemia.

High Risk for Hyperlipidemia and the Metabolic Syndrome after an Episode of Hypertriglyceridemia during 13-cis Retinoic Acid Therapy for Acne: A Pharmacogenetic Study

Context Isotretinoin (Accutane, Roche, Basel, Switzerland) is the treatment of choice for severe acne that is resistant to topical treatment. Approximately 20% of patients develop marked elevations in triglyceride levels. The mechanism responsible for isotretinoin-induced hyperlipidemia is unknown. Contribution This study showed that isotretinoin-induced hypertriglyceridemia identifies patients at high risk for chronic hyperlipidemia, truncal obesity, and hyperinsulinemia. The apoE gene and 2 and 4 alleles were more common in patients with isotretinoin-induced hypertriglyceridemia than in patients who had no lipid abnormalities while taking the drug. Implications People with isotretinoin-induced hypertriglyceridemia have increased risks for chronic hyperlipidemia and the metabolic syndrome that are possibly related to the apoE gene. The Editors Lipid abnormalities have been associated with the use of various pharmacologic agents, including -blockers, diuretics, estrogens, HIV-1 protease inhibitors (1), and 13-cis retinoic acid (isotretinoin [Accutane], Roche, Basel, Switzerland) (2, 3). Isotretinoin is the treatment of choice for severe acne resistant to other treatments. In some patients (20%), isotretinoin causes a marked but reversible elevation in plasma concentrations of triglyceride-rich lipoproteins, which can result in acute pancreatitis (4). The severity of this complication has prompted dermatologists to systematically monitor fasting plasma lipid levels whenever they prescribe isotretinoin. The mechanism for isotretinoin-induced hyperlipidemia remains elusive, and it is not known why only a fraction of persons develop this side effect. It is possible that isotretinoin elevates plasma triglyceride levels in patients with acne who have a latent, possibly familial and genetic predisposition to hyperlipidemia. The most common form of familial lipid disorders is familial combined hyperlipidemia (5). This condition shares a series of features with the metabolic syndrome, a multifaceted condition characterized by hyperlipidemia, hypertension, hyperuricemia, insulin resistance, diabetes, and obesity (6-10). Familial combined hyperlipidemia and the metabolic syndrome are usually dormant during childhood and become progressively apparent in adults. Both conditions are major contributors to heart disease. Although these disorders have a familial component (5, 11), the responsible genes have not been identified. Elucidation of the genetic basis of familial combined hyperlipidemia and the metabolic syndrome has been hampered by the heterogeneity of these disorders and their incomplete penetrance, which are consistent with strong geneenvironment interactions. We reasoned that isotretinoin is an environmental trigger that unmasks a latent familial predisposition to hyperlipidemia and the metabolic syndrome. To test our hypothesis, we used a family-based cross-sectional comparison. We initially identified a large group of young adults who had developed a pronounced elevation in plasma triglyceride levels during isotretinoin therapy for acne (hyperresponders) and an equally large group whose plasma triglyceride levels had not changed during therapy (nonresponders). All participants were reevaluated for markers of the metabolic syndrome while not receiving therapy. Parents of hyperresponders and nonresponders were also evaluated. Methods Study Design and Participants Initially, we examined the medical records of 613 persons with acne who had been treated with isotretinoin for at least 4 weeks between 1988 and 1998 at the dermatology division of CHUV University Hospital and at the practices of four dermatologists in the area of Lausanne, Switzerland. For 601 participants (98%), fasting plasma lipid levels had been measured once before initiation of isotretinoin therapy and had then been monitored monthly by the same laboratory. A total of 18 persons were excluded because they had fasting pretreatment plasma cholesterol levels of 7.0 mmol/L or more ( 271 mg/dL), triglyceride levels of 3.0 mmol/L or more ( 266 mg/dL), or both. Thus, 583 persons were included in the analysis (Figure 1). Mean duration of isotretinoin course was 6 months, and an average of six lipid values were available for each participant during treatment. We determined isotretinoin-associated changes in fasting plasma triglyceride level by calculating the difference between the highest value recorded during isotretinoin therapy and the pretreatment level. Hyperresponders (n = 117) were identified as persons who had developed an increase in plasma triglyceride level of 1.0 mmol/L or more ( 89 mg/dL) (corresponding to the upper quintile in the distribution); 145 participants whose plasma triglyceride levels had remained unchanged or decreased during isotretinoin therapy (a difference 0.1 mmol/L [ 9 mg/dL], corresponding to the lower quartile in the distribution) were considered nonresponders. We contacted the hyperresponders and the nonresponders and asked them to participate in our study and to be reevaluated while not receiving therapy. Only 15 hyperresponders and 45 nonresponders were not found or declined to participate. Participation rate was higher for hyperresponders (87%) than nonresponders (69%) (P = 0.001) because of difficulties in motivating healthy persons who had shown no change in plasma lipid levels during isotretinoin therapy. A total of 102 hyperresponders and 100 nonresponders were reevaluated while not receiving therapy. We also contacted the parents of these participants (when both parents were available) and eventually recruited both parents of 71 hyperresponders and 60 nonresponders. The procedures were in accordance with institutional guidelines. The local Ethics Committee approved the protocol, and each participant provided informed consent. Figure 1. Flow chart of the study. Measurements Participants filled out a questionnaire and had a physical examination, including measurement of height, body weight, waist-to-hip ratio, and blood pressure (evaluated using a sphygmomanometer while participants were seated for 10 minutes). Fat mass was estimated by bioelectric impedance using the Bio-Z generator (Eugdia, Paris, France), as described elsewhere (12). Venous blood was collected on EDTA after a 12-hour fast and was processed within 2 hours. Nineteen parents receiving lipid-lowering therapy were asked to stop therapy at least 1 week before they were examined. The clinical chemistry laboratory of Lausanne University Medical Policlinic performed biochemical measurements, as described elsewhere (1). Genomic DNA was isolated from peripheral blood cells, and a series of sequence variations was examined by using polymerase chain reaction amplification and restriction digest, according to published protocols: the 2, 3, and 4 alleles within the apoE gene (13); the Pro12Ala polymorphism within the peroxisome proliferator-activated receptor (PPAR)- gene (14); the C to A substitution at position 278 within the 5 flanking region of the cholesterol 7-hydroxylase (CYP7-) gene (15); and the SstI, XmnI and MspI polymorphisms within the apoAI-CIII-AIV genes (16). Statistical Analyses Data are presented as the mean (SD). Statistical analyses were performed by using SPSS, version 10.0 (SPSS, Inc., Chicago, Illinois). We used t-tests, or Wilcoxon rank-sum tests when appropriate, to compare clinical characteristics. For comparison of frequency distribution, we used the chi-square test or the Fisher exact test. Logistic regression analysis was used to calculate the risk for metabolic disorders associated with a previous elevation in plasma triglyceride levels during isotretinoin therapy. The same type of analysis was performed to evaluate the risk in hyperresponders and nonresponders having one or two parents with metabolic disorders. Role of the Funding Sources None of the funding sources had any role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to submit the manuscript for publication. Results Changes in Plasma Triglyceride Levels during Isotretinoin Therapy Isotretinoin-associated changes in fasting plasma triglyceride level ranged from 0.95 mmol/L (84 mg/dL) to 3.75 mmol/L (332 mg/dL). Average change was 0.57 0.67 mmol/L (50 59 mg/dL). Compared with nonresponders (n = 100), hyperresponders (n = 102) had similar pretreatment body weight (63.3 9.6 kg vs. 64.4 11.4 kg; P > 0.2) and plasma levels of total cholesterol (4.6 0.8 mmol/L [176 32 mg/dL] vs. 4.8 1.0 mmol/L [186 37 mg/dL]; P = 0.07) and triglycerides (1.1 0.4 mmol/L [101 38 mg/dL] vs. 1.2 0.5 mmol/L [104 42 mg/dL]; P > 0.2). Hyperresponders had received a 10% higher dosage of isotretinoin (0.53 0.11 mg/kg of body weight vs. 0.59 0.14 mg/kg of body weight; P = 0.003). Characteristics of Hyperresponders and Nonresponders When Not Receiving Isotretinoin Therapy Hyperresponders and nonresponders were reevaluated 3.8 2.5 years (median, 4 years) after completion of isotretinoin therapy. Mean age was 27.4 7.2 years (range, 16 to 49 years; median, 26 years). In contrast to the pretreatment period, hyperresponders had a higher body mass index and higher fasting plasma concentrations of total cholesterol and triglycerides than nonresponders (Table 1). Moreover, waist-to-hip ratio; fat mass content; systolic blood pressure; plasma levels of low-density lipoprotein cholesterol, apolipoprotein B, and insulin; ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol; and ratio of insulin to glucose were all higher in hyperresponders. Table 1. Characteristics of Hyperresponders and Nonresponders and Their Parents While Not Receiving Isotretinoin Therapy To further characterize the relationship between the lipid response to isotretinoin therapy and the subsequent development of metabolic disorders, we performed logistic regression analysis, using age, sex, apoE genotype, and dose of isotretinoin as covariates (Figure 2). This analysis ind

Inactivated hepatitis A vaccine booster given ≥24 months after the primary dose

We investigated what happens with the immune response when people come back for their booster dose of inactivated hepatitis A vaccine later than the recommended time of 6-12 months after the primary dose. We recruited a group of 124 travellers who received either the primary doses of Havrix 720 (two doses) or of Havrix 1440 (one dose) >/=24 months before study entry. They received a booster dose of Havrix 1440 and blood was drawn 1 month later. As a control group, we recruited a group of 125 travellers who followed a recommended schedule with a primary dose at month 0 and a booster dose at months 6-12. For both study groups, the GMTs increased dramatically and similarly upon the booster immunisation. Although significantly more late travellers (32%) had lost detectable antibodies than controls (11%) before administration of the booster dose, all these subjects showed an anamnestic response to the booster dose. Delaying the booster dose up to 66 months after primary vaccination did not seem to influence the immunogenicity of the booster dose. However, the recommended 6-12-month interval remains if detectable antibody titers are to be warranted constantly.

High prevalence of cardiovascular risk factors in the Seychelles (Indian Ocean).

In recent years, increasingly high rates of cardiovascular diseases have been recorded in the Seychelles. A survey was performed to investigate the prevalence of cardiovascular risk factors in that population, which is shifting from its traditional habits to a westernized lifestyle. The Seychelles population is of predominantly black African origin. A sex- and age-stratified random sample of 1,309 subjects was drawn from 21,256 people aged 25-64 years. A response rate of 86% was achieved. The data showed a high prevalence of hypertension (25%) and cigarette smoking (54%) in men and a high prevalence of hypertension (20%) and obesity (21%) in women. Hypercholesterolemia (greater than 6.5 mmol/l) was found in 9% of men and 15% of women. High density lipoprotein cholesterol levels (mean +/- SD) were higher in men (1.42 +/- 0.49 mmol/l) than in women (1.36 +/- 0.34 mmol/l). High levels of lipoprotein(a) (mean +/- SD) were found both in men (319 +/- 362 mg/l) and women (328 +/- 415 mg/l). The high prevalence of cardiovascular risk factors identified in the Seychelles indicates a pressing current need for effective preventive strategies.

Postischemic Blood Flow Response in Hypercholesterolemic Patients

We undertook this cross-sectional study to compare the mechanical behavior and postischemic response of the radial artery of 15 newly diagnosed hypercholesterolemic patients with those of 15 age- and sex-matched normocholesterolemic control subjects and 21 hypercholesterolemic patients treated for 2 years with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 10 to 20 mg/d). At the time of the study total cholesterol levels were at 7.9 +/- 0.2, 4.9 +/- 0.2, and 6.0 +/- 0.3 mmol/L in the three groups, respectively (mean +/- SEM, P < .001). High-resolution, noninvasive echotracking for assessment of internal arterial diameter was combined with measurements of blood flow velocity by Doppler and blood pressure by photoplethysmography. Radial cross-sectional compliance and distensibility were similar in all groups. Forearm blood flow and flow-mediated dilation were measured after a 5-minute upper arm occlusion. Flow was calculated from the vessel diameter and blood flow velocity recorded simultaneously at the same site. Flow-mediated dilation after ischemia was not significantly different among the three groups. However, forearm blood flow increase was markedly blunted (P < .01) in untreated hypercholesterolemic patients (211%) compared with the normocholesterolemic control subjects (411%) and treated patients (365%). These findings suggest that the distensibility of the radial artery, a muscular conduit vessel usually devoid of atherosclerotic lesions, and its flow-mediated dilation are preserved in hypercholesterolemic patients. In contrast, forearm resistance vessels exhibit a markedly reduced postischemic blood flow response that may be restored by prolonged lipid-lowering intervention.