Pascal Chavanet

Does hepatitis C virus co-infection accelerate clinical and immunological evolution of Hiv-infected patients?

Objective:To study the influence of hepatitis C virus (HCV) co-infection on clinical and immunological evolution of HIV-infected patients. Design:A longitudinal study of HIV-infected individuals with or without HCV infection, identified at the Infectious Diseases Department of Dijon University Hospital and enrolled in a historical cohort, was performed. Methods:One hundred and nineteen HIV-infected people co-infected with HCV and 119 matched individuals infected with HIV alone were included in the cohort (median participation time 3 years; range, 2 months to 11.5 years). Clinical progression was defined as one or more of the following: a 30% decrease in the Karnofsky index; a 20% loss of body weight; an AIDS-defining illness (for non-AIDS patients); death (except by accident, suicide or overdose). Immunological progression was defined as a 50% decrease in the initial CD4 T-cell count (for patients with an initial count > 100 × 106 cells/l). Effects of HCV co-infection were evaluated using Kaplan-Meier survival analysis and significance was tested using univariate (log-rank and Petos tests) and multivariate methods (Coxs model). Results:In univariate analysis, immunological progression was not statistically different between the HCV-positive group and the HCV-negative group, whereas clinical progression was significantly faster in HCV-positive patients (P < 0.005, log–rank test). In a multivariate Cox model, clinical progression remained significantly associated with infection by HCV [hazard ratio (HR), 1.64; 95% confidence interval (CI), 1.06–2.55; P < 0.05]. Stratified multivariable analysis retained HCV as a significant prognostic factor of clinical progression (HR, 10.9; 95% CI, 1.09–109.3; P < 0.05) and immunological progression (HR, 2.31; 95% CI, 1.16–4.62; P < 0.02) for patients with an initial CD4 count above 600 × 106 cells/l. Conclusions:Clinical progression is more rapid in HIV–HCV co-infected patients than in HIV-seropositive patients are not infected by HCV. The prognostic value of HCV infection for both clinical and immunological progression is significant at early stages of HIV infection. These findings may argue for active management of hepatitis C infection in co-infected individuals, especially for asymptomatic patients whose CD4 count is above 600 × 106 cells/l, to predict and prevent accelerated progression of HCV and HIV diseases.

Association between Insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy

Summary: Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV‐infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross‐sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV‐HCV‐coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV‐HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV‐HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV‐HCV and HIV groups. HIV‐HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37; p = .01 and p = .003, respectively). Lipoatrophy was observed more frequently in HIV‐HCV patients in comparison with HIV patients (41% versus 14%; p = .003). In HIV‐HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

Candidemia in critically ill patients: difference of outcome between medical and surgical patients

ObjectiveCandidemia is increasingly encountered in critically ill patients with a high fatality rate. The available data in the critically ill suggest that patients with prior surgery are at a higher risk than others. However, little is known about candidemia in medical settings. The main goal of this study was to compare features of candidemia in critically ill medical and surgical patients.DesignTen-year retrospective cohort study (1990–2000).SettingMedical and surgical intensive care units (ICUs) of a teaching hospital.PatientsFifty-one patients with at least one positive blood culture for Candida species.Main resultsRisk factors were retrieved in all of the patients: central venous catheter (92.1%), mechanical ventilation (72.5%), prior bacterial infection (70.6%), high fungal colonization index (45.6%). Candida albicans accounts for 55% of all candidemia. The overall mortality was 60.8% (85% and 45.2% in medical and surgical patients, respectively). Independent factors associated with survival were prior surgery (hazard ratio [HR] =0.25; 0.09–0.67 95% confidence interval [CI], p<0.05), antifungal treatment (HR =0.11; 0.04–0.30 95% CI, p<0.05) and absence of neutropenia (HR =0.10; 0.02–0.45 95% CI, p<0.05). Steroids, neutropenia and high density of fungal colonization were more frequently found among medical patients compared to surgical ones.ConclusionsCandidemia occurrence is associated with a high mortality rate among critically ill patients. Differences in underlying conditions could account for the poorer outcome of the medical patients. Screening for fungal colonization could allow identification of such high-risk patients and, in turn, improve outcome.

The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients

BACKGROUND/AIMS The evolution of hepatitis B virus (HBV) serological patterns and the clinical relevance of isolated anti-HBc pattern are not well established in HIV infected patients. METHODS A cohort of 240 patients was followed for 6.9+/-3.4 years, with iterative HBV serologic assays performed (mean interval of 2.2 years). RESULTS Five patients without HBV markers at baseline subsequently developed positive anti-HBs (incidence 0.66/100 patient-year), as did two patients with chronic HBs antigenemia (incidence 1.66/100 patient-year). Only one patient with isolated anti-HBc pattern developed HBs chronic antigenemia. Persistent isolated anti-HBc pattern was observed in 37 patients (13 with detectable blood HBV DNA) and was strongly associated with positive hepatitis C virus (HCV) viremia (hazard ratio=9.5, confidence interval 95%: 4.5-20.0, P<0.0001). Hepatic lesions were more severe in HCV infected patients with persistent isolated anti-HBc pattern than in those without (Knodell score 9.2+/-4.6 versus 6.7+/-5.0, P=0.04). In time updated analysis, this pattern was not associated with an increased risk of hepatotoxicity, by contrast with HCV infection or positive HBs antigenemia. CONCLUSIONS In HIV infected patients, HBV serological status must be systematically and regularly assessed, and systematic HBV vaccination must be proposed in those without HBV marker. Isolated anti-HBc pattern must be considered in the management of hepatitis C, but not for antiretroviral therapy.

Cryptococcus neoformans Galactoxylomannan Contains an Epitope(s) That Is Cross-Reactive with Aspergillus Galactomannan

ABSTRACT We report a case of cryptococcosis in which a serum enzyme-linked immunosorbent assay (ELISA) for Aspergillus galactomannan was positive, with no evidence of aspergillosis. Soluble antigens from 19 Cryptococcus neoformans strains and purified carbohydrates of C. neoformans capsule were thus assayed in the Aspergillus galactomannan ELISA. Antigens from all C. neoformans strains, and purified galactoxylomannan, gave a positive reaction, suggesting that C. neoformans galactoxylomannan contains an epitope(s) that is cross-reactive with Aspergillus galactomannan.

Value of Patient Self-Report and Plasma Human Immunodeficiency Virus Protease Inhibitor Level as Markers of Adherence to Antiretroviral Therapy: Relationship to Virologic Response

Three methods of adherence to antiretroviral therapy were evaluated for 149 patients infected with human immunodeficiency virus (HIV): plasma level of protease inhibitors (PIs), patient self-report, and routine biological parameters associated with the use of some antiretroviral drugs. Adherence to therapy was estimated from a score calculated from answers to a self-administered questionnaire and on the basis of measurement of relevant plasma and blood levels. Of the 149 patients, 112 had a virologic response, and 122 had adequate trough PI levels. Plasma PI levels and virologic outcome were significantly correlated (P<.0001). The adherence score was significantly correlated with virologic response (P<.001). Macrocytosis was significantly associated with virologic response in the patients treated with zidovudine or stavudine (P=.006). PI level was the higher significant predictor of virologic response (P=.0003). Self-reported adherence (P=.01) and macrocytosis (P=.05) were also independently associated with antiretroviral efficacy.

Evaluation of the Patient Medication Adherence Questionnaire As a Tool for Self-Reported Adherence Assessment in HIV-Infected Patients on Antiretroviral Regimens

Abstract Purpose: Adherence to antiretroviral medications is critically important for the success of therapy in patients treated for HIV infection. Patient self-report is a simple method to measure and explore adherence. Even though a variety of surveys have been developed to monitor self-reported adherence, there is no standardized instrument that may be used in routine clinical practice. The usefulness of the Patient Medication Adherence Questionnaire (PMAQ) was evaluated in HIV-infected patients on protease inhibitor (PI)-containing regimens. Method: Data from 149 patients were collected. Study participants completed the PMAQ and provided blood samples to measure plasma HIV-1 RNA concentrations and trough plasma levels of PI. Patients were considered adherent if they had a virologic response and/or had an adequate trough plasma level of PI. Results: A close relationship was found between patient reports of adherence during the previous 4 days and objective measures such as HIV RNA level and plasma levels of PI. Motivation with regard to antiretroviral treatment, confidence in personal skills, and an optimistic attitude to life were identified as important determinants of adherence. On the other hand, sociodemographic background, social support, alcohol and illicit drug use, bothersome symptoms, and depression were not associated with a lower medication adherence. Conclusion: Patients’ psychological and behavioral factors are central in the acceptance and adherence to antiretroviral therapy. To improve the feasibility and the reproducibility of the PMAQ, we propose a revised form of the PMAQ, focusing on the variables identified as strong predictors of adherence.

Cross-sectional study of the susceptibility of Candida isolates to antifungal drugs and in vitro-in vivo correlation in HIV-infected patients.

Objectives:To investigate (1) the frequency of clinical resistance to oral polyenes or azole treatment for oral candidiasis, (2) the frequency of resistant in vitro Candida strains, (3) the relationship between the susceptibilities of in vitro Candida species and in vivo status in HIV patients.Design:Prospective cross-sectional study.Setting:Tertiary care clinic at Bocage Hospital, Dijon, France.Patients:HIV-infected patients with and without oral candidiasis.Interventions:Clinical examination, oral swab for mycologic investigations.Main outcome measures:Clinical diagnosis of oral candidiasis, identification of the antifungal treatment given within the previous month, identification of Candida species, antimycogramm and determination of the minimal inhibitory concentration (MIC) for fluconazole, and measurement of T-helper cell count.Results:Within a 2-month period, 154 HIV-infected patients were studied: 46 heterosexuals, 51 intravenous drug users (IVDU), 52 homosexuals and five blood transfusion recipients. The percentages of patients with oral candidiasis were: 41, 80, 44 and 20%, respectively (P<0.05); the mean T-helper cell counts were 200, 135, 210 and 238×106/l cells, respectively (P <0.05). Twenty-two patients (14.3%) had received recent azole treatment and 29 (18.8%) recent oral polyene treatment. Among the 84 patients with and the 70 patients without oral candidiasis, 78 and 28 Candida strains were isolated, respectively. Although Candida albicans represented the majority of Candida species (88 strains, 83%), the non-albicans strains were isolated more frequently in patients who had received recent antifungal treatment. No strains were resistant to ketoconazole, miconazole or econazole; however, six (5.6%), 16 (15%) and 10 (9.5%) were intermediately susceptible to the three drugs, respectively. Twelve (1 3.6%) of the 88 C. albicans, five of the six C. (Torulopsis) glabrata, one of the five C. tropicalis and all three C. krusei strains were resistant to fluconazole. These resistant strains were separated as follows: 41.1% of C. albicans strains resistant to fluconazole were isolated from patients who had received recent azole therapy, 1 7.6% from patients who received recent oral polyene, and 3.7% from patients who had not received any recent antifungal treatment (P= 0.004). The mean MIC of these three categories of isolates were 3.6, 1.6 and 0.6mg/l, respectively (P=0.06).Conclusions:Oral candidiasis and fluconazole-resistant Candida isolates are more frequently found in IVDU. Treatments using azoles select non-albicans strains and are associated with decreased susceptibilities of C. albicans strains to fluconazole in particular. These findings show that prolonged azole treatment in severely immunocompromised patients should be avoided.

Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy

ABSTRACT For some pneumococci the fluoroquinolone MICs are low but the mutant prevention concentrations (MPCs) are high; this difference defines in vitro the mutant selection window (MSW). We investigated in vivo the bacterial reduction and the occurrence of resistant mutants with moxifloxacin (MFX; 400 mg once daily) or levofloxacin (LVX; 500 mg twice daily) in treatments similar to those in humans with experimental pneumonia due to pneumococci (expPP) exhibiting various MICs and MPCs. The MIC/MPC for MFX and LVX and genotypes were as follows: strain 16089, 0.125/0.125 and 0.5/0.5 (wild type); strain MS1A, 0.25/0.25 and 1/2 (efflux); strain MS2A, 0.25/4 and 1.75/28 (parC79); strain MR3B4, 0.25/4 and 2/32 (parC79); strain M16, 0.5/2 and 8/32 (parC83); strain Gyr-1207, 1.5/3 and 8/16 (gyrA); and strain MQ3A, 4/4 and 16/64 (parC and gyrA). Both drugs were efficient with wild type-expPP, but only MFX was efficient with efflux-expPP. No bacterial reduction was observed for parC-expPPs due to mutants observed in 18 to 100% of animals, depending on the strain and the drug tested. These mutants showed unbound area under the concentration-time curve and MICs of from 50 to 164 for MFX. The in vivo pharmacodynamic boundaries of the MSW were different for MFX and LVX. We conclude that, after LVX or MFX treatment, mutants occur in vivo if there is a preexisting parC mutation, since the drug concentrations fall below the MPCs of these strains. Since the MPC determination cannot be routinely determined, these phenotypes or genotypes should be detected by simple tests to guide the therapeutic options.

Acute bacterial prostatitis: heterogeneity in diagnostic criteria and management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis.

BackgroundThere is currently a lack of consensus for the diagnosis, investigations and treatments of acute bacterial prostatitis (AP).MethodsThe symptoms, investigations and treatments of 371 inpatients diagnosed with AP were analyzed through a retrospective study conducted in four departments – Urology (U), Infectious Diseases (ID), Internal Medicine (IM), Geriatrics (G) – of two French university hospitals.ResultsThe cause of admission, symptoms, investigations and treatments depended markedly on the department of admission but not on the hospital. In U, patients commonly presented with a bladder outlet obstruction, they had a large imaging and functional check-up, and received alpha-blockers and anti-inflammatory drugs. In ID, patients were febrile and received longer and more appropriate antibiotic treatments. In G, patients presented with cognitive disorders and commonly had post-void urine volume measurements. In IM, patients presented with a wide range of symptoms, and had very diverse investigations and antibiotic regimen.Overall, a 3:1 ratio of community-acquired AP (CA-AP) to nosocomial AP (N-AP) was observed. Urine culture isolated mainly E. coli (58% of AP, 68% of CA-AP), with venereal agents constituting less than 1%. The probabilistic antibiotic treatments were similar for N-AP and CA-AP (58% bi-therapy; 63% fluoroquinolone-based regimen). For N-AP, these treatments were more likely to be inadequate (42% vs. 8%, p < 0.001) and had a higher rate of bacteriological failure (48% vs. 19%, p < 0.001).Clinical failure at follow-up was more common than bacteriological failure (75% versus 24%, p < 0.001). Patients older than 49 had more underlying urinary tract disorders and a higher rate of clinical failure (30% versus 10%, p < 0.0001).ConclusionThis study highlights the difficulties encountered on a daily basis by the physicians regarding the diagnosis and management of acute prostatitis.