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Objectives: Increased risk of cardiovascular disease in patients infected with HIV has been attributed to immune activation, inflammation, and immunosenescence, all of which are linked to chronic immune activation by viral infections, particularly cytomegalovirus (CMV). Our aim is to evaluate the impact of these atherogenic markers in HIV-infected patients who never smoked., Design: Exposure-matched, cross-sectional study., Methods: In 59 HIV-infected individuals [n = 30 undergoing ≥4 years of antiretroviral therapy (ART); n = 29 never treated with ART] and 30 age-matched HIV-negative controls, we measured the level of activation and senescence, as well as the frequency of CMV-specific T cells, on peripheral blood mononuclear cells, while examining their association with carotid intima-media thickness. Partial correlations were adjusted for age, systolic blood pressure, and nadir CD4 cell count., Results: The previously described roles of T-cell activation, CMV, and immunosenescence in the atherosclerotic risk of HIV-infected patients, as assessed by carotid intima-media thickness, were not apparent in our cohort of particularly 'healthy' HIV-infected never-smokers., Conclusion: In HIV-infected individuals at low cardiovascular disease risk, our data show that the increased risk of carotid atherosclerosis is not associated with immunological markers described to be associated with HIV disease progression.

In order to improve knowledge on Escherichia coli bacteraemia during pregnancy, we studied clinical data and performed molecular characterization of strains for 29 E. coli bacteraemia occurring in pregnant women. Bacteraemia mostly occurred in the third trimester of pregnancy (45%) and was community-acquired (79%). Portals of entry were urinary (55%) and genital (45%). E. coli strains belonged mainly to phylogroups B2 (72%) and D (17%). Four clonal lineages (i.e. sequence type complex (STc) 73, STc95, STc12 and STc69) represented 65% of the strains. The strains exhibited a high number of virulence factor coding genes (10 (3-16)). Six foetuses died (27%), five of them due to bacteraemia of genital origin (83%). Foetal deaths occurred despite adequate antibiotic regimens. Strains associated with foetal mortality had fewer virulence factors (8 (6-10)) than strains involved in no foetal mortality (11 (4-12)) (p 0.02). When comparing E. coli strains involved in bacteraemia with a urinary portal of entry in non-immunocompromised pregnant vs. non-immunocompromised non-pregnant women from the COLIBAFI study, there was no significant difference of phylogroups and virulence factor coding genes. These results show that E. coli bacteraemia in pregnant women involve few highly virulent clones but that severity, represented by foetal death, is mainly related to bacteraemia of genital origin., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

Background: While residual plasma viremia is commonly observed in HIV-infected patients undergoing antiretroviral treatment (ART), little is known about its subclinical consequences., Methods: This cross-sectional study included 47 male, never-smoking, non-diabetic patients with ≥4 years of ART and controlled HIV-replication (HIV-viral load, VL <20 copies/mL for ≥1 year). Residual HIV-VL was measured using an ultrasensitive assay (quantification limit: 1 copy/ml). Patients were categorized as having detectable (D; 1-20 copies/mL, n = 14) or undetectable (UD; <1 copies/mL, n = 33) HIV-VL. Linear regression was used to model the difference in total carotid intima-media thickness [c-IMT, measures averaged across common carotid artery (cca), bifurcation, and internal carotid artery] and cca-IMT alone across detection groups. Multivariable models were constructed for each endpoint in a forward-stepwise approach., Results: No significant differences were observed between viremia groups with respect to median ART-duration (9.6 years, IQR = 6.8-10.9), nadir CD4+T-cell (208/mm3, IQR = 143-378), and CD4+T-cell count (555/mm3, IQR = 458-707). Median adjusted inflammatory markers tended to be higher in patients with D- than UD-viremia, with differences in IL-10 being significant (p = 0.03). After adjustment on age, systolic blood pressure, and insulin resistance, mean cca-IMT was significantly lower in patients with undetectable (0.668 mm±0.010) versus detectable viremia (0.727 mm±0.015, p = 0.002). Cca-IMT was also independently associated with age and insulin resistance. Mean adjusted total c-IMT was no different between viremia groups (p = 0.2), however there was large variability in bifurcation c-IMT measurements., Conclusions: Higher cca-IMT was observed in patients with detectable, compared to undetectable, HIV-VL in never-smoking ART-controlled patients, suggesting that residual HIV viremia may be linked to atherosclerosis.

The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120,000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/&#95;fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: To determine whether the reported increased atherosclerotic risk among HIV-infected individuals is related to antiretroviral therapy (ART) or HIV infection, whether this risk persists in never-smokers, and whether inflammatory profiles are associated with higher risk., Design: Matched cross-sectional study., Methods: A total of 100 HIV-infected patients (50 ART-treated >4 years, 50 ART-naive but HIV-infected >2 years) and 50 HIV-negative controls were recruited in age-matched never-smoking male triads (mean age 40.2 years). Carotid intima-media maximal thickness (c-IMT) was measured across 12 sites. Pro-inflammatory [highly sensitive C-reactive protein (hs-CRP), resistin, interleukin-6, interleukin-18, insulin, serum amyloid A, D-dimer) and anti-inflammatory (total and high molecular weight adiponectin, interleukin-27, interleukin-10) markers were dichotomized into high/low scores (based on median values). c-IMT was compared across HIV/treatment groups or inflammatory profiles using linear regression models adjusted for age, diabetes, hypertension, and, for HIV-infected patients, nadir CD4 cell counts., Results: Although adjusted c-IMT initially tended to be thicker in ART-exposed patients (P=0.2), in post-hoc analyses stratifying by median HIV duration we observed significantly higher adjusted c-IMT in patients with longer (>7.9 years: 0.760±0.008 mm) versus shorter prevalent duration of known HIV infection (<7.9 years: 0.731±0.008 mm, P=0.02), which remained significant after additionally adjusting for ART (P=0.04). Individuals with low anti-inflammatory profile (median score) had thicker c-IMT (0.754±0.006mm versus 0.722±0.006 mm, P<0.001), with anti-inflammatory markers declining as prevalent duration of HIV infection increased (P for linear trend <0.001)., Conclusion: Known HIV duration is related to thicker c-IMT, irrespective of ART, in these carefully selected age-matched never-smoking HIV-treated and ART-naive male individuals. Higher levels of anti-inflammatory markers appeared protective for atherosclerosis.

The efficacy and tolerance of telaprevir (TVR) was examined in 20 mostly cirrhotic HIV-hepatitis C genotype 1 (HCV-G1)-infected patients failing previous treatment with pegylated-interferon and ribavirin (PR). HCV-RNA less than 12 IU/ml was observed in 35.3% of patients at W2, 55.0% at W4, 65.0% at W12 and 55.0% at W24. All patients with virological failure (n = 9) exhibited V36M/R155K mutations. Early virological response was a determinant of HCV-RNA less than 12 IU/ml at W24 (P < 0.001). No grade 3-4 dermatological side-effects were reported. TVR-PR tritherapy appeared to be rather effective and well tolerated among difficult-to-treat HIV-HCV-G1 patients.

Pre-exposure prophylaxis currently has no market authorisation in France, but is still evaluated. This article presents an additional tool for risk reduction, currently the subject of studies.

The outcome of bacterial bloodstream infections during pregnancy has greatly improved over the last few decades. However, there are no recent data on the characteristics of bacteremia in pregnant women. The aim of this study was to describe clinical and microbiological features of bacteremia and to assess maternal and fetal outcome. This retrospective study was conducted in the obstetrics departments of five teaching hospitals in Paris, France, from 2005 to 2009. The incidence of bacteremia was 0.3%. The most common sources of bacteremia were chorioamnionitis (47%) and the most common pathogen isolated was Escherichia coli. Empirical antimicrobial therapy was inappropriate in 29% of bacteremia cases, mostly (65%) when secondary to infection with an aminopenicillin-resistant microorganism. Bacteremia during pregnancy was associated with a 10% fetal mortality. Bacteremia during pregnancy is a rare occurrence, but it is associated with an unexpectedly poor fetal outcome and a high mortality rate.

Objectives: We aimed to determine the effectiveness of boosted protease inhibitor monotherapy (BPIMT) initiated as a maintenance strategy in routine care and identify predictive factors of failure., Design: Observational study in the FHDH-ANRS CO4 cohort., Methods: Five hundred and twenty-nine virologically suppressed individuals switched to BPIMT in the period 2006-2010, 75% had at least 12 and 49% at least 24 months of follow-up. Virological failure (two consecutive HIV-RNA > 50 copies/ml or one HIV-RNA > 50 copies/ml followed by BPIMT discontinuation) and treatment failure (virological failure, antiretroviral reintensification or death) were analysed separately., Results: At baseline, 11% were protease inhibitor-naive, median duration on combined antiretroviral therapy was 84 months and median duration of suppressed viremia was 38 months. Nine percent had a history of virological failure, while on a protease inhibitor-containing regimen, and rates of virological failure were higher among those individuals [adjusted hazard ratio, 1.6; 95% confidence interval (CI), 0.9-2.9]. Compared to individuals with less than 1 year of sustained virological suppression before the switch to BPIMT, those with longer duration were less likely to experience virological failure [hazard ratio, 0.7; (95% CI, 0.4-1.2) and 0.6 (95%CI, 0.4-0.9)] for a duration of 12-23 months and 24 months or more, respectively. Rates of failure were similar for BPIMT with lopinavir-ritonavir (RTV) or darunavir-RTV, but increased for BPIMT with atazanavir-RTV. Same risk factors were associated with treatment failure., Conclusion: The safety and efficacy of a maintenance strategy with BPIMT in a routine care setting matched the results of randomized clinical trials. A longer duration since last virological rebound before switching to BPIMT was associated with a decreased risk of subsequent failure.

Background: In HIV-infected patients, data on immunogenicity of Yellow fever immunization are scarce, and there is conflicting evidence of the influence of CD4 T-cell count and plasma HIV RNA on neutralizing antibody titer (NT) after vaccine injection., Methods: In this prospective cohort study, NT was measured in all consecutive HIV outpatients who had previously received at least 1 injection of Yellow fever vaccine. Risk factors for vaccine failure (NT < 1:10) and magnitude of NT according to dates of HIV diagnosis and immunization were assessed by logistic regression and general linear models., Results: Among 364 included patients, 24 (7%) had NT <1:10 after a mean delay of 8.4 years after immunization. Among patients immunized after HIV diagnosis (n = 240), NT <1:10 was associated only with detectable plasma HIV RNA at immunization. Among 79 patients with primary vaccination after diagnosis of HIV infection, higher HIV RNA at immunization was the unique independent risk factor for NT <1:10 [adjusted odds ratio (OR) = 3.73 per log10, 95% confidence interval (CI): 1.14 to 12.28]. Lower values of NT were independently associated with a shorter duration of undetectable plasma HIV RNA (OR = 1.05 per year, 95% CI: 1.005 to 1.09) and higher plasma HIV RNA (OR = 0.91 per log10, 95% CI: 0.84 to 0.99) at immunization., Conclusions: The key determinant of antibody response was the HIV replication status at immunization. No association was found between antibody response and CD4 T-cell count.

Background: The unparalleled success of combination antiretroviral therapy (cART) is based on the combination of three drugs from two classes. There is insufficient evidence whether simplification to ritonavir boosted protease inhibitor (PI/r) monotherapy in virologically suppressed HIV-infected patients is effective and safe to reduce cART side effects and costs., Methods: We systematically searched Medline, Embase, the Cochrane Library, conference proceedings and trial registries to identify all randomised controlled trials comparing PI/r monotherapy to cART in suppressed patients. We calculated in an intention to treat (loss-of follow-up, discontinuation of assigned drugs equals failure) and per-protocol analysis (exclusion of protocol violators following randomisation) and based on three different definitions for virological failure pooled risk ratios for remaining virologically suppressed., Findings: We identified 10 trials comparing 3 different PIs with cART based on a PI/r plus 2 reverse transcriptase inhibitors in 1189 patients. With the most conservative approach (viral load <50 copies/ml on two consecutive measurements), the risk ratios for viral suppression at 48 weeks of PI/r monotherapy compared to cART were in the ITT analysis 0.94 8 (95% CI 0.89 to 1.00) p = 0.06; risk difference -0.06 (95%CI -0.11 to 0) p = 0.05, p for heterogeneity  = 0.08, I(2) = 43.1%) and in the PP analysis 0.93 ((95%CI 0.90 to 0.97) p<0.001; risk difference -0.07 (95%CI -0.10 to -0.03) p<0.001, p for heterogeneity  = 0.44, I(2) = 0%). Reintroduction of cART in 44 patients with virological failure led in 93% to de-novo viral suppression., Interpretation: Virologically well suppressed HIV-infected patients have a lower chance to maintain viral suppression when switching from cART to PI/r monotherapy. Failing patients achieve high rates of de-novo viral suppression following reintroduction of reverse transcriptase inhibitors.

Objectives: We evaluated a monotherapy maintenance regimen with lopinavir/ritonavir versus continuing current combined antiretroviral treatment (cART) in HIV patients with suppressed plasma HIV-1 RNA., Patients and Methods: This was an open-label, non-inferiority, multicentre trial in 23 sites in France. Adults were randomized if they had no history of virological failure while receiving a protease inhibitor, maintained HIV-1 RNA <50 copies/mL for at least 6 months and did not change cART during the last 3 months. The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (non-inferiority margin set at -12%) with missing data and treatment modification considered as failure. The trial has been registered in ClinicalTrials.gov under the identifier NCT00140751., Results: At Week 48, 84% (73/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group [difference, -4.0%, lower limit of 90% two-sided confidence interval (CI) for difference, -12.4%]. In secondary analysis with success defined as plasma HIV-1 RNA <400 copies/mL, 87% (76/87) of patients in the lopinavir/ritonavir monotherapy group were virologically suppressed compared with 88% (87/99) in the cART group (difference, -0.5%, lower limit of 90% two-sided CI for difference, -8.5%). If antiretroviral treatment intensification was taken into account, 91% (79/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group (difference, +2.9%, lower limit of 90% two-sided CI for difference, -4.5%). Failures of lopinavir/ritonavir monotherapy did not show acquired resistance mutations in the protease gene., Conclusions: Lopinavir/ritonavir monotherapy did not achieve non-inferiority versus cART for maintaining plasma HIV-1 RNA <50 copies/mL. Nevertheless, the incidence of virological failure was low (mostly with HIV-1 RNA <400 copies/mL) and easily managed by treatment intensification.

HIV-1 RNA level and darunavir concentration in the genital tract were measured in 45 men receiving darunavir-ritonavir mono- or tritherapy. At week 48, a low frequency (3/45) of HIV-1 RNA shedding was observed in patients (1 on monotherapy and 2 on triple therapy), although they had undetectable HIV-1 RNA in plasma. The median darunavir seminal plasma concentration was close to the blood plasma free fraction, demonstrating a good penetration of darunavir into the male genital tract.

We examined factors associated with virological failure in 310 HIV-infected patients receiving atazanavir (ATV). Independent links were identified with virological failure under ATV: virological failure previous history (P = 0.006) and ATV underdosing (P = 0.04). A maintenance therapy was protective (P = 0.01). The optimal therapeutic ranges of ATV concentration were found to be from 300 ng/ml (or 180 for patients treated with maintenance therapy) to 650 ng/ml for C24 and from 1000 ng/ml (or 500 for patients treated with maintenance therapy) to 2000 ng/ml for C12.

Objective: To determine characteristics and risk factors for unmasking tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRIS) following initiation of combination antiretroviral therapy (cART) in HIV-infected patients, which have not yet been assessed to date., Design: Retrospective single-center cohort study., Methods: Medical records of HIV-infected patients diagnosed with tuberculosis following cART initiation were reviewed. Cases of unmasking IRIS were identified using provisional consensus definitions. Characteristics of patients with and without unmasking TB-IRIS were compared. A case-control design was used to identify risk factors for unmasking TB-IRIS in patients initiating cART., Results: Among 47 patients on cART at TB diagnosis, 11 experienced unmasking IRIS (23%). They had lower CD4% (9 vs. 14, P=0.02), higher HIV-RNA load at baseline (5.2 vs. 4.0 log, P=0.005), and a stronger CD4% increase with HIV-RNA decline after 1 month on cART (+7 vs. +3 log, P=0.02, and -3.2 vs. -0.8 log, P=0.005) than the 36 remaining patients without unmasking IRIS. In the case-control study, risk factors for unmasking IRIS were African country of origin (65 vs. 18%, P=0.007), higher baseline HIV-RNA load (5.2 vs. 4.7 log, P=0.01), stronger CD4% increase (+7 vs. +2, P=0.0001), and HIV-RNA decline of more than 3 log after 1 month on cART (73 vs. 27%, P=0.02)., Conclusion: Patients with African origins, advanced HIV infection, or a strong response to cART are at greater risk of unmasking TB-IRIS.

Objective: To describe features of reactive haemophagocytic syndrome (RHS) in HIV-1-infected adult patients. To compare characteristics of patients with malignancy-associated RHS and infection-associated RHS., Design and Setting: Retrospective study in three departments of Infectious Diseases/Internal Medicine at three French tertiary centres., Patients and Methods: Medical charts of HIV-1-infected adult patients and RHS seen between January 2006 and December 2007 were reviewed. Demographic, clinical and laboratory data obtained at the time of RHS episode were compared between patients with malignancy-associated RHS and infection-associated RHS using non-parametric tests. The overall survival was assessed using the Kaplan-Meier method., Results: Fifty-eight HIV-1-infected patients were diagnosed with RHS [certain RHS n = 43, possible RHS n = 15, median (range) age 42 (23-85) years, men 76%]. At time of RHS, the median duration of HIV infection was 4 (0-22) years and 57% received HAART. The median CD4 lymphocyte count was 91 (2-387)/microl and 35% of patients had a plasma HIV-1 RNA less than 50 copies/ml. Underlying haemopathy/malignancy (Hodgkin lymphoma n = 10) or infection (tuberculosis n = 9, cytomegalovirus infection n = 5) were evidenced for 31 and 23 patients, respectively. Patients with haemopathy/malignancy-associated RHS presented more frequently with splenomegaly (97 vs. 70%, P < 0.01), lower aspartate aminotransferase (36 vs. 84 UI/l, P < 0.01) and lactate dehydrogenase (530 vs. 911 UI/l, P < 0.01) levels and CD8 cell count (234 vs. 588/microl, P < 0.01). Eighteen (31%) patients died. The overall survival was not statistically different between the two groups (P = 0.68)., Conclusion: In the HAART era, RHS is frequently associated with underlying haemopathy/malignancy, especially Hodgkin lymphoma. The prognosis remains poor but seems, however, better than in the pre-HAART era.

Objectives: The emergence of non-AIDS-related events in the HIV-infected population experiencing a longer life expectancy implies the implementation of a comprehensive approach of HIV clinical management through better access to care, prevention, and early diagnosis of co-morbidities., Methods: The Orchestra program is a computer-assisted HIV care and support tool implemented since December 2004 in the outpatient clinic of a University Hospital set in Paris, France. The intervention aims at improving access to HIV information care and support specifically targeted five areas of actions: cardiovascular risk factors; gynecological follow-up; anti-hepatitis B virus (HBV) vaccine coverage; sexuality and prevention of sexually transmitted infections; and compliance to antiretrovirals. The impact of this program was examined prospectively on a "before-after" basis after a two-year implementation., Results: In the two-year period, 1717 patients were regularly followed. The level of the database information significantly increased in time (low density lipoprotein (LDL) cholesterol and glycemia were informed in 74% of patients at inclusion versus 95% at two years, and 83% versus 97%, p < 0.001, respectively). The number of targeted interventions was also higher. For eligible women, papanicolaou smears and mammography were prescribed in 52% of cases after intervention, versus 44% at inclusion, p0.04 and 83% versus 50%, p < 0.001, respectively. Indicators of care eventually improved significantly. Initially 72% non-adherent patients declared to be adherent after the intervention ( p < 0.001) and 67% of patients with initial LDL-hypercholesterolemia normalized their LDL level within two years ( p < 0.001)., Conclusion: The Orchestra program has provided a unique opportunity to assess and improve prevention and management of co-morbidities in HIV patients.

Background: The French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac trial showed that a strategy combining a 7-valent pneumococcal conjugate vaccine (PCV) prime at week 0 followed by a 23-valent pneumococcal polysaccharide vaccine (PPV) boost at week 4 enhances the frequency and magnitude of immunoglobulin (Ig) G responses against Streptococcus pneumoniae polysaccharides (SPPs) compared with PPV alone. CD4 T cell responses specific to the diphtheria-derived carrier protein CRM(197) were evaluated., Methods: Lymphocyte proliferative responses (LPRs) and T(H)1 cytokine T cell responses against the diphtheria-derived carrier protein CRM(197) contained in the PCV were investigated at weeks 0, 4, and 24., Results: In the prime-boost PCV and PPV group, the magnitude of LPRs to diphtheria toxoid and CRM(197) increased at week 4 (P < .001) and persisted until week 24 (P = .08 and .13, respectively, compared with week 4). Interferon-gamma and interleukin-2 production to CRM(197) increased significantly at week 4 (P = .02 and P < .001, respectively) and remained stable until week 24 (P = .28 and P = .08, respectively). No changes were detected in the PPV group. A strong association among the magnitude of LPRs to CRM(197) at week 4, the breadth of SPP specific IgG responses at week 8 (P = .03), and sustained IgG responses at week 24 was observed. A high frequency of helper follicular CD4(+)CXCR5(+) T cells at baseline was associated with a better LPR response to CRM(197.), Conclusions: The PCV prime-elicited memory T cell responses were associated with better and sustained humoral SPP specific IgG responses. ClinicalTrials.gov identifier. NCT00148824.

Background: Data on liver fibrosis evolution in HIV-HBV-coinfected patients treated with tenofovir disoproxil fumarate (TDF) are scarce. The effect of TDF on liver fibrosis in 148 HIV-HBV-coinfected patients was prospectively evaluated using Fibrometer∆ scores and liver biopsies in a subset of patients., Methods: The mean change from baseline (Δ) in Fibrometer score was modelled using a generalized estimating equation. Homogeneous continuous-time Markov models were used to study risk factors for regression or progression of liver fibrosis., Results: Median follow-up of patients treated with TDF was 29.5 months (25th-75th percentile 20.9-38.1). The distribution of scored fibrosis at TDF initiation was F0-F1 n=65, F2 n=37 and F3-F4 n=46. In patients with a baseline fibrosis score of F3-F4, Fibrometer score decreased with a triphasic shape (Fibrometer Δ at 12, 24 and 36 months after TDF initiation was -0.079, -0.069 and -0.102, respectively). Despite duration on TDF, higher fibrosis scores were noted in F3-F4 patients with high HBV viral load and HDV coinfection, and in F0-F2 patients who had high HBV viral load and low CD4(+) T-cell count. Progression in fibrosis score over time was influenced by age, alcohol consumption, low CD4(+) T-cell count and HCV coinfection, whereas HDV coinfection and longer duration of HBV infection prevented fibrosis regression. No influence of antiretrovirals other than TDF was found., Conclusions: The use of TDF in HIV-HBV-coinfected patients led to a decrease in liver fibrosis score in patients with advanced fibrosis or cirrhosis. Sustainability of its direct antiviral and indirect antifibrotic effects on the liver need to be studied further.

Background: It is debated whether a risk of protease inhibitor mutation selection in proviral DNA exists during intermittent HIV-1 viraemia thereby impacting long-term virological control., Methods: Virologically controlled patients treated with lopinavir/ritonavir were included in a 48 week pilot trial during which lopinavir/ritonavir dosage was reduced if lopinavir concentration was >5000 ng/mL at inclusion. Serum lipids were longitudinally assessed and proviral DNA was quantified and sequenced in patients experiencing transient viraemia., Results: Thirty-three virologically suppressed patients while on a lopinavir/ritonavir-containing regimen were included, of whom 28 [20 males, mean age 44.6 years (SD 10.9)] completed the 48 week follow-up as scheduled. A significant decrease in lopinavir level was noted [mean C(min), 7363 ng/mL (min, 5118; max, 12 415) at baseline versus 4319 ng/mL (min, 1427; max, 8683) at week 48, P < 0.03]. A significant decrease in triglycerides was also observed [1.73 mmol/L (SD 1.08) at baseline versus 1.34 mmol/L (SD 0.91) at week 48, P = 0.03], whereas no significant change occurred for total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. In the 15 patients with transient viraemia, analysis of proviral DNA for antiretroviral resistance showed that mutations had occurred when compared with baseline genotypes in three patients: I47M (n = 2) and M46I (n = 1). Selection of these mutations was not associated with virological failure as all three patients had a sustained virological response without treatment modification after a 3 year follow-up., Conclusions: This pilot study evaluating the biochemical and virological impact of a reduced dosing of lopinavir/ritonavir suggests that lower exposure to lopinavir/ritonavir could be associated with a significant decrease in triglycerides during treatment, without occurrence of resistance mutations that might impact the virological response to treatment.

Background: Among patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection, salvage regimens including enfuvirtide have demonstrated sustained efficacy. Because of reluctance to use subcutaneous injections, raltegravir may be an alternative to replace enfuvirtide within a suppressive regimen. We conducted a prospective, randomized, open-label trial to compare the antiviral efficacy and safety of a switch to raltegravir with the efficacy and safety of continuing enfuvirtide., Methods: A total of 170 patients with multidrug-resistant HIV-1 infection and plasma HIV-1 RNA levels <400 copies/mL who were receiving enfuvirtide-based regimens were randomized 1:1 to maintain enfuvirtide or to switch to raltegravir. The primary efficacy end point was the cumulative proportion of patients with virologic failure, defined as a confirmed plasma HIV-1 RNA level >or=400 copies/mL, over 24 weeks. The secondary end points mainly involved safety., Results: The switch to raltegravir was non-inferior to the maintenance of enfuvirtide, with virologic failure rates of 1.2% in both treatment arms in the intention-to-treat analysis (beta = 0.01%; 95% confidence interval, -6.7 to 6.8) and 1.2% and 0%, respectively, in the on-treatment analysis (beta = 1.22%; 95% confidence interval, -5.6 to 8.1). At week 24, 88%-89% of patients in both arms had plasma HIV-1 RNA levels <50 copies/mL. No significant CD4 cell count changes occurred in either arm. Grade 3-4 adverse events and laboratory abnormalities were uncommon and were not different between the treatment arms., Conclusion: A switch to raltegravir was safe, well tolerated, and virologically non-inferior to the maintenance of enfuvirtide in patients infected with multidrug-resistant HIV-1 infection who were receiving suppressive antiretroviral therapy., Clinical Trials Registration: NCT00454337

Objectives: Liver function is a key component of efavirenz metabolism and might be altered in severe liver fibrosis induced by HIV/chronic hepatitis co-infection. However, data evaluating the impact of liver fibrosis stages on the plasma efavirenz level are lacking., Patients and Methods: In this study, conducted in 134 HIV-infected patients [77, 35 and 22 HIV mono-infected, HIV/hepatitis C virus (HCV) co-infected and HIV/hepatitis B virus (HBV) co-infected, respectively] treated with efavirenz 600 mg once a day in combination with other antiretroviral agents, plasma concentration was measured at least 8 h after the last drug intake using a validated HPLC method. The degree of liver fibrosis was determined by means of either liver biopsy or non-invasive biochemical markers (Fibrotest. The proportions of patients above a threshold of 4000 ng/mL were compared by means of Pearson's chi(2) test or Fisher's exact test., Results: In HIV mono-infected and HIV/HCV and HIV/HBV co-infected patients, mean +/- SD efavirenz plasma concentrations were 3060 +/- 1928, 4108 +/- 3324 and 3163 +/- 2432 ng/mL, respectively. The proportion of patients with an efavirenz concentration above 4000 ng/mL differed significantly according to the presence of hepatitis and the fibrosis stage. A concentration above 4000 ng/mL was found in 14 patients (18.2%) mono-infected with HIV compared with 5 (22.7%, P = 0.01) and 9 (25.7%, P = 0.001) HIV/HBV or HIV/HCV co-infected patients, respectively. When the fibrosis stage was considered in all patients with hepatitis, 3 cirrhotic patients (42.6%) had an efavirenz concentration above the 4000 ng/mL threshold [compared with 14 (18.2%) HIV mono-infected patients, P = 0.001]., Conclusions: Therapeutic drug monitoring may be of interest in cirrhotic patients more at risk of side effects due to efavirenz overdosing.

Metabolic disorders are a major concern during antiretroviral therapy, especially for their potential to increase cardiovascular disease risk. In a multicenter, prospective study conducted in patients exposed to an antiretroviral regimen including lopinavir boosted with ritonavir, an early and sustained increase of high-density lipoprotein cholesterol was observed over a 72-week period. This increase was positively correlated with the exposure to lopinavir/ritonavir during the first 24 weeks.

Background: Campylobacter bacteremia is uncommon. The influence of underlying conditions and of the impact of antibiotics on infection outcome are not known., Methods: From January 2000 through December 2004, 183 episodes of Campylobacter bacteremia were identified in 23 hospitals in the Paris, France, area. The medical records were reviewed. Characteristics of bacteremia due to Campylobacter fetus and to other Campylobacter species were compared. Logistic regression analysis was performed to identify risk factors for fatal outcome within 30 days., Results: Most affected patients were elderly or immunocompromised. C. fetus was the most commonly identified species (in 53% of patients). The main underlying conditions were liver disease (39%) and cancer (38%). The main clinical manifestations were diarrhea (33%) and skin infection (16%). Twenty-seven patients (15%) died within 30 days. Compared with patients with bacteremia due to other Campylobacter species, patients with C. fetus bacteremia were older (mean age, 69.5 years vs. 55.6 years; P = .001) and were more likely to have cellulitis (19% vs. 7%; P = .03), endovascular infection (13% vs. 1%; P = .007), or infection associated with a medical device (7% vs. 0%; P = .02). Independent risk factors for death were cancer (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.2-20.8) and asymptomatic infection (OR, 6.7; 95% CI, 1.5-29.4) for C. fetus bacteremia, the absence of prescription of appropriate antibiotics (OR, 12.2; 95% CI, 0.9-157.5), and prescription of third-generation cephalosporins (OR, 10.2; 95% CI, 1.9-53.7) for bacteremia caused by other species., Conclusions: Campylobacter bacteremia occurs mainly in immunocompromised patients. Clinical features and risk factors of death differ by infection species.

Human immunodeficiency virus (HIV) infection is a risk factor for thrombotic microangiopathy (TMA). We sought whether a severe deficiency in ADAMTS13, the enzyme specifically involved in the cleavage of von Willebrand factor, was associated with specific presenting features and outcome in HIV-associated TMA. In this prospective, multicentre, case-control study, 29 patients of 236 in the French Network on TMA had an HIV-associated TMA. Seventeen patients with severe ADAMTS13 deficiency (ADAMTS13 <5% HIV(+) group) were compared to 12 patients with a detectable ADAMTS13 activity (ADAMTS13 >or=5% HIV(+) group). HIV(+) patients were also compared to 62 patients with idiopathic TMA, either with (45 patients, ADAMTS13 <5% idiopathic group) or without (17 patients, ADAMTS13 >or=5% idiopathic group) severe ADAMTS13 deficiency. ADAMTS13 <5% HIV(+) patients had less AIDS-related complications than ADAMTS13 >or=5% HIV(+) patients (23.5% versus 91.6%, respectively, P = 0.0005) and their median CD4(+) T cell count was higher (P = 0.05). TMA-associated death rate was higher in ADAMTS13 >or=5% HIV(+) patients than in ADAMTS13 <5% HIV(+) patients (50% versus 11.7%, respectively, P = 0.04). In ADAMTS13 <5% patients, TMA-associated death rate was comparable between HIV(+) and idiopathic patients (15.5% in idiopathic patients, P-value was non-significant). By contrast, TMA-associated death rate in ADAMTS13 >or=5% HIV(+) patients was higher than in idiopathic patients (11.7% in idiopathic patients, P = 0.04). In conclusion, HIV-associated TMA with severe ADAMTS13 deficiency have less AIDS-related complications and a higher CD4(+) T cell count. TMA prognosis is better and comparable to this of idiopathic forms.

Objectives: The Saint-Antoine Orchestra Program aims at improving the clinical management of HIV-infected patients through access to care, prevention and early diagnosis of comorbidities., Methods: The program was initiated in December 2004 on the whole database. The following topics were concerned: cardiovascular risk factors, gynecological follow-up, anti-HBV vaccinal coverage, sexuality and prevention of STIs, therapeutic adherence and counsels to travelers. The program included several actions: diffusion of information to patients, development of a computerized chart (alert pop-ups), individualized prescription advice and recommendations for specialist referral., Results: The program was applied to 1959 patients whose initial characteristics were: mean age: 43+/-10 years; ratio M/W: 1466/493; European origin: 69%; sub-Saharan: 19%; mean duration of HIV infection: 9.3+/-6 years; naïve of antiretrovirals: 14%; mean CD4+count: 494+/-277/mm(3); HIV viral load inferior to 50 cp/ml: 62%. Among 1347 patients for whom cardiovascular risk factors were completely informed, 42% had two or more factors. In particular, 31% of them were smokers, 7% had an arterial pressure superior to 140/90 mmHg and 11% had LDL-cholesterolemia superior to 4.1 mmol/l. Among 1448 untreated patients, 70% were initially considered as adherent. Half of the concerned women had neither cervical smear nor mammography up to date. Among 67% patients with an informed complete HBV serology, 27% were seronegative among which 310 (86%) were eligible for the vaccine. Problems of sexual difficulties or prevention were initially discussed for 11% of patients. Among them, 14% had a problem of prevention and 148 (66%) recognized sexual difficulties., Conclusion: The initiation of the Saint-Antoine Orchestra program has provided a unique opportunity to assess and improve the prevention and management of comorbidities in HIV patients. Also, this program aimed to improve professional practices.

Among protease inhibitors, atazanavir has not been associated with urolithiasis in clinical studies. We describe 11 cases of atazanavir-associated urolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients with low water intake, high urinary pH, and a prior history of urinary stones may have a higher risk of atazanavir-associated urine crystallization.

Objective: To determine the incidence, clinical characteristics, microbiological features and outcome of Mycobacterium xenopi infections in patients attending a university hospital., Methods: We reviewed the files of HIV-seronegative patients meeting ATS criteria for M. xenopi pulmonary infection between 1993 and 2004., Results: Ten patients were studied (7 men, 60+/-27 years). All but one had underlying chronic health disorders (chronic lung disease, cancer, alcoholism, systemic steroid therapy). The clinical and radiological findings were those associated with tuberculosis. Acid-fast bacilli were detected by direct examination in 9 cases, and antituberculous treatment prescribed in 8 patients. Specific treatment was started an average of 60+/-25 days after sampling, and generally combined a fluoroquinolone, clarithromycin and rifampicin, with or without ethambutol, for a mean of 11.4 months (1-37 months). Five patients had surgical excision (diagnostic in 1 case). Four patients died of their underlying disease. Two patients recovered with antibiotics alone and three with antibiotics and surgery. One patient was lost to follow-up after five months., Conclusion: Pulmonary infection by M. xenopi is rare in HIV-seronegative patients. The prognosis depends mainly on the patient's underlying health status. Surgery is an important component of treatment.

Acquired human immunodeficiency virus type 1(HIV-1) resistance to the fusion inhibitor enfuvirtide (ENF) is primarily associated with mutations within the highly conserved first heptad repeat (HR1) region of gp41. Viral env sequences, however, are remarkably variable, and the envelope genetic background could have an important impact on optimal expression of HR1 mutations. We have examined the genetic evolution of env sequences, ENF susceptibility, and Env replicative capacity in patients failing ENF treatment. Sequential plasma-derived virus populations, obtained from six patients initiating ENF treatment as part of a salvage therapy, were studied using a recombinant phenotypic assay evaluating the entire gp120 and the gp41 ectodomains. Regardless of major differences in the baseline ENF susceptibilities, viral populations with similar phenotypic ENF resistance (50% inhibitory concentration, >3,000 ng/ml) were selected under treatment in four of six patients. As expected, in all patients ENF-resistant viruses harbored one or more HR1 mutations (positions 36, 38, and 43). Interestingly, in five patients the emergence of resistance mutations was not associated with reduced Env replicative capacity. Phylogenetic analysis of env sequences in sequential samples from two patients showed that the HR1 mutations had emerged in the context of env quasi-species that were different from those prevalent at baseline. Thus, the envelope genetic context appears to play a critical role in the selection of HR1 mutations and the expression of ENF resistance, thereby conditioning the evolution of HIV-1 under fusion inhibitor selective pressure.

We report the case of a Colombian immunosuppressed migrant hospitalized in France with fever, dry cough and altered general health. Results of blood culture and bronchoalveolar lavage led to the diagnosis of the first reported case of concomitant disseminated histoplasmosis and pulmonary coccidioidomycosis in an HIV-infected patient.

In this study, the dynamics of CD4 cell depletion during tenofovir/didanosine co-administration were analysed. Ninety-five HIV-positive patients were followed for 562 days, and 37 lost at least 50 CD4 cells, with a median delay of 274 days. Cox analysis showed that the CD4 cell decrease was associated with a duration of treatment by didanosine of more than 853 days and a didanosine dose of more than 5.50 mg/kg.

Fluoroquinolone (FQ) utilization should be optimized, with the aim of controlling both multidrug-resistant bacteria and costs. In the present study, the appropriateness of FQ prescriptions for urinary tract infections (UTIs) before and after an educational intervention was examined prospectively. FQ-prescribing physicians received oral and written guidelines between the two phases of the study. All patients admitted to Saint-Antoine University Hospital (Paris) and treated with FQs for UTIs during the study period were included. The main outcome measures of the appropriateness of FQ prescriptions were based on the principles of Antibiotic Utilization Review. The study involved 127 patients. The main prescribing errors before the intervention were wrong routes of administration and failure to take into account antibiotic susceptibility results. The rate of erroneous prescriptions fell by 74.4% after intervention. About 71% of the improvement can be attributed to the intervention (71.4%; 95% confidence interval, 39.3-86.8). The intervention had an overall positive impact on FQ prescription quality. The decrease in inappropriate prescriptions was due mainly to the use of antibiotic susceptibility results (23% vs. 11.5%, P<0.05) and better consideration of indications (18.9% vs. 3.8%; P<0.05). Future educational interventions will cover other indications and will take into account costs and local antimicrobial susceptibility patterns.

Objectives: To assess the use of microbiological examinations, notably serology, in the etiological diagnosis of pulmonary diseases in a department of infectious diseases., Methods: A retrospective study assessing the habits of microbiological examination prescriptions in pulmonary infections was carried out from 1/05/2000 to 31/10/2001. All patients admitted during this period for pulmonary infection diagnosis and treatment in the infectious diseases and tropical Unit of Saint Antoine Hospital (Paris), were included. The relevance of use of the following diagnostic procedures was assessed: cytobacteriological examination of sputum, specimens obtained on bronchoscopy, hemoculture, serology and search for Legionella urinary antigens. Factors having influenced the co-prescription of these microbiologic examinations were analysed., Results: The survey concerned 179 patients: 7 acute bronchitis, 25 acute exacerbations of chronic bronchitis and 147 community-acquired pneumonia. Microbiological diagnosis was obtained for 34 patients (17.4%), primarily on respiratory specimens. Serology was prescribed in 61 cases with a second serology in 23% (14/61). The principal factor predictive of bacterial serology prescription was the existence of interstitial opacity on chest radiography. Likewise, the search for Legionella urinary antigens was associated with the presence of interstitial opacity on the X-ray and of hyponatremia. However, it was only carried out in 37% of pneumonia with serious clinical presentation (25/67) and was followed by the prescription of combined antibiotics in 70% of the cases (40/57)., Conclusion: Assessment of the microbiology diagnostic methods of pulmonary infections showed the misuse of serology and insufficient prescription of the search for Legionella urinary antigens, recommended in the case of serious clinical signs.

Background: Our aim was to identify factors predisposing HIV-infected patients on long-term antiretroviral therapy (ART) to major hypertriglyceridemia (HTG)., Patients and Methods: We conducted a retrospective, case-control study involving 76 HIV-infected patients with HTG, defined by 12-hour fasting plasma triglyceride (TG) > 4.5 mmol/l on at least one occasion, and 150 HIV-infected matched control patients with TG consistently below 1.8 mmol/l., Results: Patients coinfected by the hepatitis C virus appeared to be protected from HTG. In addition to known predisposing factors for HTG in HIV-infected patients (ART and immune/viral status), patients with a history of excess body weight were twice as likely to have HTG (odds ratio [OR] 2.8, 95% confidence interval [CI]: 1.1-6.9); HTG was also more frequent in patients who had a first-degree relative with cardiovascular disease (CVD) or a major risk factor for CVD (OR = 3.6, CI: 1.3-9.9)., Conclusion: By identifying subgroups of highly predisposed patients, appropriate lifestyle and dietary measures could be recommended on ART initiation.

Objective: To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed., Methods: The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model., Results: Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76-6.90), randomization to the genotyping arm (OR=2.13, 1.20-3.79), prescription of lamivudine (OR=1.69, 1.01-2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02-2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13-0.68), a high baseline viral load (OR=0.37, 0.28-0.50), the presence of at least five PI mutations (OR=0.42, 0.26-0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39-0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41-0.99)., Conclusions: These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3-6 2002 (Abstract N(o)133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7-11 2002 (Abstract N(o)ThOrB138).

Objective: To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir., Methods: All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method., Results: In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score., Conclusions: We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

Objective: 1. to assess the impact of highly active antiretroviral therapy (HAART) on the occurrence of bacteraemia in HIV-infected patients and their clinical and microbiological characteristics. 2. to identify risk factors for bacteraemia in this setting., Methods: The files of all HIV-infected patients hospitalized for an episode of bacteraemia in a 28-bed infectious diseases unit between January 1995 and December 1998 were reviewed. Cases occurring during HAART were compared to cases occurring in patients not receiving HAART. Furthermore, in a case-control study, patients with bacteraemia occurring during HAART were compared with other patients receiving HAART., Results: There were 74 episodes of bacteraemia in patients not receiving HAART and 31 episodes in patients receiving HAART. The occurrence of bacteraemia fell from 10.5/100 hospitalizations in 1995 to 5.5/100 in 1998 (P = 0.02 trend test). The occurence of P. aeruginosa bacteraemia fell sharply (9/398 vs 1/273, P = 0.05). A significant fall in catheter-related infections was observed between 1995 and 1998 (5.5% vs 1.8%). The two-thirds/one-third distribution of hospital-acquired and community-acquired infections remained stable throughout the period study. In patients receiving HAART, the case-control study showed by multivariate analysis, that a CD4 cell count of less than 100/ micro L [OR = 7.3 (1.9-49.7)], and the use of exogenous devices [OR = 13.3 (2.5-71)] were significantly associated with the risk of bacteraemia., Conclusion: The introduction of HAART has been associated with a significant fall in the occurrence of bacteraemia. However, patients with a low CD4 cell count remain at risk of bacteraemia with similar microbiological and epidemiological characteristics than in the pre-HAART era.

Objective: Peripheral venous catheter (PVC)-associated complications were prospectively evaluated in a 2 month-study performed in 3 different wards., Methods: For each inserted PVC, the following complications were observed daily by an external investigator: tenderness, erythema, swelling or induration, palpable cord and purulence. PVC that were removed were systematically sent to the Microbiology department and analysed according to the semi-quantitative method described by Brun-Buisson et al., Results: A total of 525 PVC (corresponding to 1,036 catheterisation-days) were included. Main clinical complications were erythema (22.1%), tenderness (21.9%), swelling or induration (20.9%), palpable cord (2.7%) and purulence (0.2%). Phlebitis, defined by 2 or more of the following signs: tenderness, erythema, swelling or induration and palpable cord, was observed in 22%. Catheter colonization (> or = 103 CFU/ml) occurred in 13%. Bacteria isolated from colonized catheters were coagulase-negative staphylococci (88.1%), Staphylococcus aureus (7.1%) and Candida sp. (4.8%). Multivariate risk factor analysis showed that age > or = 55 y. (OR = 3.16, p = 0.003), insertion on articulation site (OR = 2.94, p = 0.01) or in jugular vein (OR = 8.18, p = 0.01) and > 72 hour-catheterisation (OR = 4.74, p = 0.0003) were significantly associated with PVC colonization. Risk factors for phlebitis were skin lesions (OR = 1.88, p < 0.016), active infection unrelated to PVC (OR = 2.8, p = 0.001), "poor quality" peripheral vein (OR = 2.46, p < 0.02) and > 72 hour-catherisation (OR = 2.38, p = 0.009)., Conclusion: Complications associated with peripheral venous catheters are frequent but remain benign. They could probably be reduced by a systematic change every 72-96 hours as recommended by different guidelines.

Ritonavir (RTV) strongly increases the concentrations of protease inhibitors (PIs) in plasma in patients given a combination of RTV and another PI. This pharmacological interaction is complex and poorly characterized and shows marked inter- and intraindividual variations. In addition, RTV interacts differently with saquinavir (SQV), indinavir (IDV), amprenavir (APV), and lopinavir (LPV). In this retrospective study on 542 human immunodeficiency virus-infected patients, we compared inter- and intraindividual variability of plasma PI concentrations and correlations between the C(min) (minimum concentration of drug in plasma) values for RTV and the coadministered PI C(min) values. Mean RTV C(min)s are significantly lower in patients receiving combinations containing APV or LPV than in combinations with SQV or IDV. With the most common PI dose regimens (600 mg of IDV twice a day [BID], 800 mg of SQV BID, and 400 mg of LPV BID), the interindividual C(min) variability of patients treated with a PI and RTV seemed to be lower with APV and LPV than with IDV and SQV. As regards intraindividual variability, APV also differed from the other PIs, exhibiting lower C(min) variability than with the other combinations. Significant positive correlations between RTV C(min) and boosted PI C(min) were observed with IDV, SQV, and LPV, but not with APV. Individual dose adjustments must take into account the specificity the pharmacological interaction of each RTV/PI combination and the large inter- and intraindividual variability of plasma PI levels to avoid suboptimal plasma drug concentrations which may lead to treatment failure and too high concentrations which may induce toxicity and therefore reduce patient compliance.

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C(min,ss)) was 1.92 microg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 microg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C(max,ss)) was 7.12 microg/ml, the area under the concentration-time curve from 0 to 10 h (AUC(0-10)) was 32.06 microg. h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC(ss)) was 35.74 microg. h/ml. Decreases in the mean values of C(min,ss) (29%), C(max,ss) (42%), AUC(0-10) (42%), and AUC(ss) (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C(min,ss) markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C(min,ss) above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.