Patrick Taffé

Gilbert Syndrome and the Development of Antiretroviral Therapy–Associated Hyperbilirubinemia

BACKGROUND Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice. METHODS We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years. RESULTS The estimated average bilirubin level was 8.8 micromol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 mu mol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 micromol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 micromol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had > or =2 episodes of hyperbilirubinemia in the jaundice range (>43 micromol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1. CONCLUSIONS Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.

Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection

Background:The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. Objectives:To determine whether single-nucleotide polymorphisms (SNPs) in TLR2–4 and TLR7–9 influenced the natural course of HIV-1 infection. Methods:Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation–maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). Results:Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7–9.2] for GA versus AA and OR, 4.7 (95% CI,1.9–12.0) for GG versus AA (P = 0.0008). Conclusion:Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Molecular Epidemiology Reveals Long-Term Changes in HIV Type 1 Subtype B Transmission in Switzerland

BACKGROUND Sequence data from resistance testing offer unique opportunities to characterize the structure of human immunodeficiency virus (HIV) infection epidemics. METHODS We analyzed a representative set of HIV type 1 (HIV-1) subtype B pol sequences from 5700 patients enrolled in the Swiss HIV Cohort Study. We pooled these sequences with the same number of sequences from foreign epidemics, inferred a phylogeny, and identified Swiss transmission clusters as clades having a minimal size of 10 and containing >or=80% Swiss sequences. RESULTS More than one-half of Swiss patients were included within 60 transmission clusters. Most transmission clusters were significantly dominated by specific transmission routes, which were used to identify the following patient groups: men having sex with men (MSM) (38 transmission clusters; average cluster size, 29 patients) or patients acquiring HIV through heterosexual contact (HETs) and injection drug users (IDUs) (12 transmission clusters; average cluster size, 144 patients). Interestingly, there were no transmission clusters dominated by sequences from HETs only. Although 44% of all HETs who were infected between 1983 and 1986 clustered with injection drug users, this percentage decreased to 18% for 2003-2006 (P<.001), indicating a diminishing role of injection drug users in transmission among HETs over time. CONCLUSIONS Our analysis suggests (1) the absence of a self-sustaining epidemic of HIV-1 subtype B in HETs in Switzerland and (2) a temporally decreasing clustering of HIV infections in HETs and IDUs.

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.

Improving Blood Pressure Control Through Pharmacist Interventions: A Meta-Analysis of Randomized Controlled Trials

Background Control of blood pressure (BP) remains a major challenge in primary care. Innovative interventions to improve BP control are therefore needed. By updating and combining data from 2 previous systematic reviews, we assess the effect of pharmacist interventions on BP and identify potential determinants of heterogeneity. Methods and Results Randomized controlled trials (RCTs) assessing the effect of pharmacist interventions on BP among outpatients with or without diabetes were identified from MEDLINE, EMBASE, CINAHL, and CENTRAL databases. Weighted mean differences in BP were estimated using random effect models. Prediction intervals (PI) were computed to better express uncertainties in the effect estimates. Thirty‐nine RCTs were included with 14 224 patients. Pharmacist interventions mainly included patient education, feedback to physician, and medication management. Compared with usual care, pharmacist interventions showed greater reduction in systolic BP (−7.6 mm Hg, 95% CI: −9.0 to −6.3; I2=67%) and diastolic BP (−3.9 mm Hg, 95% CI: −5.1 to −2.8; I2=83%). The 95% PI ranged from −13.9 to −1.4 mm Hg for systolic BP and from −9.9 to +2.0 mm Hg for diastolic BP. The effect tended to be larger if the intervention was led by the pharmacist and was done at least monthly. Conclusions Pharmacist interventions – alone or in collaboration with other healthcare professionals – improved BP management. Nevertheless, pharmacist interventions had differential effects on BP, from very large to modest or no effect; and determinants of heterogeneity could not be identified. Determining the most efficient, cost‐effective, and least time‐consuming intervention should be addressed with further research.

High Prevalence of Peripheral Arterial Disease in HIV-Infected Persons

BACKGROUND Atherosclerosis has been assessed in human immunodeficiency virus (HIV)-infected persons by using various methods. Peripheral arterial disease (PAD) has not been evaluated, however. We studied the cross-sectional prevalence of lower limb PAD in an HIV-infected population. METHODS PAD was assessed using the Edinburgh Claudication Questionnaire and by measuring the systolic ankle-brachial blood pressure index (ABI) at rest and after exercise. Patients with PAD were further evaluated by duplex scan of lower limb arteries. RESULTS Ninety-two consecutive HIV-infected patients were evaluated (23.9% women; mean age, 49.5 years; 61.9% current smokers). Claudication was reported by 15.2% of the patients. PAD was found in 20.7% of the patients: 9.8% had an abnormal ABI (<0.90) at rest, and 10.9% had normal ABI at rest but a >25% decrease after exercise. Of the patients with PAD, 84.2% were investigated with duplex scan, all of whom had atherosclerotic occlusions or stenoses of the iliac or femoral arteries. Age, diabetes, smoking, and low CD4+ T lymphocyte counts were identified as independent predictors of PAD. CONCLUSIONS The prevalence of symptomatic and asymptomatic PAD is high in the HIV-infected population and is much higher than expected (prevalence in the general population, approximately 3% at 60 years). This study suggests the presence of an epidemic of PAD approximately 20 years earlier in the HIV-infected than in the general population. Larger epidemiological studies are needed to better define risk factors and to evaluate whether PAD is associated with increased mortality, as it is in the general population.

All cause mortality in the Swiss HIV Cohort Study from 1990 to 2001 in comparison with the Swiss population.

Design: Mortality within the Swiss HIV Cohort Study for the years 1990–2001 was compared with the mortality of the general Swiss population. Methods: Standardized mortality ratios (SMR) and life tables were calculated for strata defined by combinations of gender and HIV transmission group. The effect of dropouts was investigated with a sensitivity analysis and by analysing CD4 cell counts before dropout. Results: During the study period 10 977 individuals had at least one cohort visit with a median observation time of 46 months. A total of 3630 patients died and 2290 dropped out. SMR decreased from 79.3 [95% confidence interval (CI), 77.2–81.5] before the introduction of highly active antiretroviral treatment (HAART) in 1996 to 15.3 (95% CI, 14.2–16.4) thereafter. For persons who acquired HIV infection by injecting drug use (IDUs), the SMR decreased from 98.2 (95% CI, 94.9–103.5) to 40.9 (95% CI, 37.0–44.8) after 1996; for all other HIV transmission groups the SMR decreased from 69.2 (95% CI, 66.9–71.6) to 9.4 (95% CI, 8.5–10.4). Thus, IDUs had significantly lower survival in comparison with other patient groups after 1996. Patients who had started HAART during the time period in which this treatment was available, had even lower SMRs. Conclusions: Although overall survival has improved considerably since the introduction of HAART, cohort life expectancy remains below that of the Swiss population. We noted, however, substantial differences in mortality among subgroups, and the results indicate that the additional risk related to injection drug use before 1996 had been masked by HIV-associated mortality.

Rate of undesirable events at beginning of academic year: retrospective cohort study

Objective To determine whether an increase in the rate of undesirable events occurs after care provided by trainees at the beginning of the academic year. Design Retrospective cohort study using administrative and patient record data. Setting University affiliated hospital in Melbourne, Australia. Participants 19 560 patients having an anaesthetic procedure carried out by first to fifth year trainees starting work for the first time at the hospital over a period of five years (1995-2000). Main outcome measures Absolute event rates, absolute rate reduction, and rate ratios of undesirable events. Results The rate of undesirable events was higher at the beginning of the academic year compared with the rest of the year (absolute event rate 137 v 107 per 1000 patient hours, relative rate reduction 28%, P<0.001). The overall adjusted rate ratio for undesirable events was 1.40, 95% confidence interval 1.24 to 1.58. This excess risk was seen for all residents, regardless of their level of seniority. The excess risk decreased progressively after the first month, and the trend disappeared fully after the fourth month of the year (rate ratio for fourth month 1.21, 0.93 to 1.57). The most important decreases were for central and peripheral nerve injuries (relative difference 82%), inadequate oxygenation of the patient (66%), vomiting/aspiration in theatre (53%), and technical failures of tracheal tube placement (49%). Conclusions The rate of undesirable events was greater among trainees at the beginning of the academic year regardless of their level of clinical experience. This suggests that several additional factors, such as knowledge of the working environment, teamwork, and communication, may contribute to the increase.

Ambiguous Nucleotide Calls From Population-based Sequencing of HIV-1 are a Marker for Viral Diversity and the Age of Infection

The fraction of ambiguous nucleotide calls in bulk sequencing of human immunodeficiency virus type 1 (HIV-1) carries important information on viral diversity and the age of infection. In particular, a fraction of ambiguous nucleotides of >.5% provides evidence against a recent infection event <1 year ago.

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.