Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study.

UNLABELLED: Real-time shear wave elastography (SWE) is a novel, noninvasive method to assess liver fibrosis by measuring liver stiffness. This single-center study was conducted to assess the accuracy of SWE in patients with chronic hepatitis C (CHC), in comparison with transient elastography (TE), by using liver biopsy (LB) as the reference standard. Consecutive patients with CHC scheduled for LB by referring physicians were studied. One hundred and twenty-one patients met inclusion criteria. On the same day, real-time SWE using the ultrasound (US) system, Aixplorer (SuperSonic Imagine S.A., Aix-en-Provence, France), TE using FibroScan (Echosens, Paris, France), and US-assisted LB were consecutively performed. Fibrosis was staged according to the METAVIR scoring system. Analyses of receiver operating characteristic (ROC) curve were performed to calculate optimal area under the ROC curve (AUROC) for F0-F1 versus F2-F4, F0- F2 versus F3-F4, and F0-F3 versus F4 for both real-time SWE and TE. Liver stiffness values increased in parallel with degree of liver fibrosis, both with SWE and TE. AUROCs were 0.92 (95% confidence interval [CI]: 0.85-0.96) for SWE and 0.84 (95% CI: 0.76-0.90) for TE (P = 0.002), 0.98 (95% CI: 0.94-1.00) for SWE and 0.96 (95% CI: 0.90-0.99) for TE (P = 0.14), and 0.98 (95% CI: 0.93-1.00) for SWE and 0.96 (95% CI: 0.91-0.99) for TE (P = 0.48), when comparing F0-F1 versus F2- F4, F0- F2 versus F3-F4, and F0 -F3 versus F4, respectively. CONCLUSION: The results of this study show that real-time SWE is more accurate than TE in assessing significant fibrosis (≥ F2). With respect to TE, SWE has the advantage of imaging liver stiffness in real time while guided by a B-mode image. Thus, the region of measurement can be guided with both anatomical and tissue stiffness information.

Performance of real-time strain elastography, transient elastography, and aspartate-to-platelet ratio index in the assessment of fibrosis in chronic hepatitis C.

OBJECTIVE: The purpose of this article is to evaluate the diagnostic performance of transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index in assessing fibrosis in patients with chronic hepatitis C by using histologic Metavir scores as reference standard. SUBJECTS AND METHODS: Consecutive patients with chronic hepatitis C scheduled for liver biopsy were enrolled. Liver biopsy was performed on the same day as transient elastography and real-time strain elastography. Transient elastography and real-time strain elastography were performed in the same patient encounter by a single investigator using a medical device based on elastometry and an ultrasound machine, respectively. Diagnostic performance was assessed by using receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) analysis. RESULTS: One hundred thirty patients (91 men and 39 women) were analyzed. The cutoff values for transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index were 6.9 kPa, 1.82, and 0.37, respectively, for fibrosis score of 2 or higher; 7.3 kPa, 1.86, and 0.70, respectively, for fibrosis score of 3 or higher; and 9.3 kPa, 2.33, and 0.70, respectively, for fibrosis score of 4. AUC values of transient elastography, real-time strain elastography, aspartate-to-platelet ratio index were 0.88, 0.74, and 0.86, respectively, for fibrosis score of 2 or higher; 0.95, 0.80, and 0.89, respectively, for fibrosis score of 3 or higher; and 0.97, 0.80, and 0.84, respectively, for fibrosis score of 4. A combination of the three methods, when two of three were in agreement, showed AUC curves of 0.93, 0.95, and 0.95 for fibrosis scores of 2 or higher, 3 or higher, and 4, respectively. CONCLUSION: Transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index values were correlated with histologic stages of fibrosis. Transient elastography offered excellent diagnostic performance in assessing severe fibrosis and cirrhosis. Real-time elastography does not yet have the potential to substitute for transient elastography in the assessment of liver fibrosis.

No pol mutation is associated independently with the lack of immune recovery in patients infected with HIV and failing antiretroviral therapy.

An investigation was undertaken to determine whether specific pol mutations hinder long-term immune recovery regardless of virological response. In total, 826 patients with >50 HIV RNA copies/ml, who underwent genotypic resistance testing between 1 January 2000 and 31 December 2003 after >3 years of antiretroviral treatment, and were followed up for >3 years after genotypic resistance testing, were analyzed retrospectively. The outcome of the study was the lack of immune recovery after >3 years of follow-up, defined as a slope by linear regression <0. The viremia detectability ratio was defined as the number of HIV RNA values of >50 copies/ml divided by the number of HIV RNA measurements during follow-up. Logistic regression was used for univariable and multivariable analysis. Median (Q1, Q3) values at baseline were the following: age 40 (37, 45) years, years on antiretroviral therapy 4.45 (3.65, 5.47), HIV RNA 3.91 (3.39, 4.53) log(10) copies/ml, CD4+ T-cell 358 (211, 524)/µl. After 3.13 years of follow-up, 375 patients (45.4%) showed a lack of immune recovery. The risk of lack of immune recovery increased independently with increasing baseline CD4+ counts (OR=1.104 per 50-cell increase, 95% CI=1.069-1.142, P<0.0001), increasing viremia detectability ratio during follow-up (OR=1.145 per 0.1-unit increase, 95% CI=1.093-1.202, P<0.0001), and with earlier calendar years of resistance testing (overall effect: P=0.0007). In conclusion, no pol mutation is associated independently with the lack of immune recovery.

Arterial stiffness evaluation in HIV-positive patients: a multicenter matched control study.

OBJECTIVE: The purpose of this article is to assess the differences, if any, in the values of carotid artery stiffness parameters between HIV-infected subjects without known cardiovascular disease (CVD) or carotid artery plaques and HIV-uninfected control subjects matched for sex, age, body mass index, and other CVD risk factors (i.e., hypertension, hypercholesterolemia, diabetes, and cigarette smoking). Arterial stiffness is emerging as a predictor of CVD risk. By recording the blood pressure, an automated echo-tracking system implemented in ultrasound equipment allows evaluation of arterial stiffness. SUBJECTS AND METHODS: Fifty-four HIV-infected patients without a history of CVD were closely matched for sex, age, body mass index, and CVD risk factors to 54 HIV-uninfected control subjects on an individual basis. Ultrasound studies of carotid artery stiffness parameters were performed using ultrasound equipment with a linear broadband high-frequency transducer. Carotid intima-media thickness was also measured. Repeatability between operators was assessed. Nonparametric Mann-Whitney U test, chi-square statistics, Fisher exact test, Pearson correlation coefficient, and intraclass correlation coefficient were used for statistical analysis. A p value less than 0.05 was considered statistically significant. RESULTS: Except for arterial compliance in HIV-infected subjects, arterial stiffness parameters were correlated with age in both groups. Compared with matched control subjects, HIV-infected subjects showed lower arterial compliance parameter values (0.95 [interquartile range, 0.78-1.23] vs 0.76 [interquartile range, 0.62-1.00]; p = 0.0009), whereas other parameters were similar. Repeatability between operators was good. CONCLUSION: HIV-infected subjects have an arterial compliance significantly lower than that of control subjects. The impairment of carotid artery distensibility may contribute to subclinical atherosclerosis.

Pathogenesis of liver damage in HCV-HIV patients.

The coinfection of HIV and HCV has become a pathology with several distinctive characteristics. Pathogenesis of liver damage in patients with HIV and HCV coinfection is complex and multifactorial. It derives from a balance of factors which interact among themselves in a dynamic way. The reasons for the accelerated course of HIV/HCV coinfection are mainly related to two principal causes: the persistence of HCV, which depends upon alterations of cell-mediated immunity, and the activation of the immune system towards secretion of proinflammatory and profibrotic cytokines. This review will first focus on the characteristics of both these immune-mediated mechanisms, and then their implication on fibrogenesis as well as on other pathogenetic mechanisms, such as interactions between viruses and the deficit of protective mechanisms. A better knowledge of adaptive immune mechanisms, cytokine alteration, interference with host defense mechanisms, and the "cross-talk" among the viruses will improve the understanding of the pathogenetic mechanism and provide the opportunity to cure this disease.

Rational design, preparation and characterization of recombinant Ag85B variants and their glycoconjugates with T-cell antigenic activity against Mycobacterium tuberculosis.

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from Mycobacterium tuberculosis. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.

[Tuberculosis meningitis in adults: 5 cases]. / Meningite tubercolare negli adulti: 5 casi clinici.

Tuberculosis still represents a problem of public health of worldwide importance. Tuberculosis meningitis is a rare yet serious infectious disease. The diagnosis is mainly clinical and should be considered in a specific epidemiological context. Culture of Mycobacterium tuberculosis from cerebrospinal fluid is required for definitive diagnosis but it cannot always be obtained. In this study we report five cases of tuberculosis meningitis admitted to our Department of Infectious and Tropical Diseases over the last six years, highlighting the main aspects that steered us towards diagnosis and the difficulties we encountered.

Area-under-the-curve for peginterferon alpha-2a and peginterferon alpha-2b is not related to body weight in treatment-naive patients with chronic hepatitis C.

One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response. This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently: peginterferon alpha-2a is flat-dosed at 180 microg regardless of body weight, whereas peginterferon alpha-2b is dosed by body weight at 0.5-1.5 microg/kg. Bodyweight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response. To test this hypothesis, we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported pharmacokinetics study. In total, 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks. Patients were randomly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12). Ribavirin was dosed by body weight at 1000 mg/day (< or = 75kg) or 1200 mg/day (> 75 kg). We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b. Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [coefficient of variation (CV): 37.5%] and, despite dosing by body weight, for peginterferon alpha-2b (CV: 36.8%). Thus, there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a, and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b.

Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort.

BACKGROUND: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. METHODS: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. RESULTS: Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. CONCLUSION: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects.

Shared epidemiological risks have resulted in HIV-infected populations having a high prevalence of hepatitis B virus (HBV) co-infection. Several prospective studies have investigated the impact of HBV co-infection on HIV disease progression; most of them were negative. On the contrary, there is evidence that HIV may modify the natural history of HBV infection. HIV positive subjects have higher rates of HBV chronification, higher HBV replication, lower ALT levels and lower rates of seroconversion to anti-HBe and anti-HBs. The impact of HIV co-infection on the outcome of HBV infection is still controversial, even if some studies have shown an accelerated progression towards decompensated cirrhosis in HIV co-infected subjects. HBV co-infection is a risk factor for severe hepatotoxicity during HAART. Vaccination for HBV is mandatory in nonimmune HIV subjects, however its efficacy in immunosuppressed patients is still controversial. HIV co-infection decreases the effectiveness of Interferon in the treatment of HBV infection. Because of its activity against both HBV and HIV, lamivudine is used in HIV-HBV co-infected patients at doses of 300 mg/daily and as part of an antiretroviral regimen, but the rate of sustained response is poor and HBV strains with mutations associated with lamivudine resistance occur at a rate of 20% per year. Trials of new drugs with activity against HBV, some of them with activity also against HIV, and some of them without cross-resistance with lamivudine, are now underway. Highly Active Anti-Hepatitis B Therapy will probably soon come of age.

Liver fibrosis, microbial translocation and immune activation markers in HIV and HCV infections and in HIV/HCV co-infection.

BACKGROUND: Liver fibrosis is accelerated in patients co-infected with human immunodeficiency virus and hepatitis C viruses. AIMS: We investigated the correlation between liver fibrosis, immune activation and microbial translocation. METHODS: This cross-sectional study included patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) mono-infections, HIV/HCV co-infection, and healthy controls (20 subjects/group). Peripheral blood was analysed to determine the levels of Forkhead box 3 (Foxp3) T cells, TGF-ß1, CD14 (soluble and surface isoforms), IL-17 and bacterial translocation products. These measurements were correlated to the severity of liver fibrosis, measured with the FIB-4 score and transient elastography. RESULTS: Foxp3T cell levels were significantly elevated in HIV mono-infected and co-infected groups (p<0.0005). FIB-4 and liver stiffness values inversely correlated with TGF-ß1 (p=0.0155 and p=0.0498). Bacterial DNA differed significantly in the HIV-positive compared to the other groups: HIV/HCV co-infected subjects had significantly higher serum levels of bacterial translocation products, CD14, and IL-17 levels (p<0.001). CONCLUSIONS: Fibrosis stage in HIV/HCV co-infection may be influenced by immune activation due either by viral infections or to bacterial translocation.

Overview on the incidence and the characteristics of HIV-related opportunistic infections and neoplasms of the heart: impact of highly active antiretroviral therapy.

The manifestation of cardiac involvement in the course of HIV infection has been significantly changed since the introduction of highly active antiretroviral therapy. While in the pre-highly active antiretroviral therapy era the predominant cardiac pathology was represented by localization of opportunistic infection, now new forms of heart involvement are described. Among infectious agents, viruses and bacteria caused the majority of infections. The 'classic' opportunistic agents, such as Toxoplasma, non-tuberculous mycobacteria, cytomegalovirus and Cryptococcus, have virtually disappeared. Endocarditis is still the most frequent infectious disease of the heart in HIV-infected patients, occurring mainly in drug users, and with the improvement in prognosis, the need for cardiac surgery is increasing. Tuberculosis, the incidence of which is still high in poor resources settings where antiretroviral drugs are not available, is a frequent cause of pericarditis, frequently evolving into cardiac tamponade. Recent studies suggest the direct role of HIV as the cause of myocarditis and heart vessel pathology. This finding points out the need of improving our knowledge about the pathogenesis, diagnosis and treatment of this kind of complication.

Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis c: a randomized, controlled study.

The two available pegylated interferon formulations, peginterferon alpha-2a and peginterferon alpha-2b, have different pharmacokinetic profiles; as a result they may have differing abilities to suppress the hepatitis C virus. A recently reported study by Formann and colleagues assessing early viral kinetics among 20 patients receiving peginterferon alpha-2b either once or twice weekly suggests that once-weekly administration of peginterferon alpha-2b is not sufficient for continuous exposure to interferon over 160 h. Twice-weekly administration is recommended to avoid increases in viral load as interferon levels decline prior to the end of the one-week dosing period. The objective of this study was to compare viral dynamics and pharmacokinetics between peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive chronic hepatitis C patients. Patients were randomized to receive peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12) once weekly. Serum peginterferon concentrations were measured at baseline, 24, 48, 120 and 168h. Hepatitis C virus (HCV) RNA was measured at baseline, 24, 48, 120 and 168 h during week 1 and then at 4 and 12 weeks. Peginterferon alpha-2b achieved maximal serum levels at 24 h, and then decreased rapidly. Of the 12 patients who received peginterferon alpha-2b, no drug was detectable in seven (58%) patients at 120 h and in 11 (92%) at 168 h. In contrast, peginterferon alpha-2a concentrations increased continuously over time, reaching maximal serum levels from 48 to 168 h. Drug was detectable in all 10 patients at 168 h. At weeks 1 and 4 no significant difference was observed in mean HCV RNA between the groups. However, at week 12, mean HCV RNA was significantly lower in the peginterferon alpha-2a group versus the peginterferon alpha-2b group (2.8126 vs 3.8726; P<0.01). The differences in mean HCV RNA values at 12 weeks may be related to the different absorption and distribution profiles of the two drugs. In conclusion, once-weekly administration of peginterferon alpha-2b (1.0 microg/kg/wk) may be insufficient for continuous interferon exposure; twice-weekly administration may help avoid increases in viral replication as interferon levels decline. Larger-scale studies assessing both viral kinetics and sustained virological responses are needed to confirm these observations.

Evaluation of the risk factors associated with lipodystrophy development in a cohort of HIV-positive patients.

The prevalence of lipodystrophy in an HIV-infected population and the risk factors associated with body shape changes were analysed in this study. Five hundred and four subjects were included. Among these, 201 (39.9%) had features of lipodystrophy syndrome (cases); 303 (60.1%) constituted the control group. Compared with the control group, the lipodystrophy subjects were different in age (P = 0.01); duration of antiretroviral therapy (P < 0.001); length of exposure to nucleoside reverse transcriptase inhibitors (NRTIs) (P < 0.001) and to protease inhibitors (P < 0.001); nadir of CD4 cell count (P < 0.001); and value of plasma HIV-RNA before antiretroviral therapy (P = 0.008). In a multivariate analysis, length of therapy and a nadir CD4 cell count below 250 cell/microl were associated with an increased risk of lipodystrophy. Among patients with lipodystrophy, isolated fat loss was observed in 46 (23%); isolated fat accumulation in 40 (20%); mixed (loss and accumulation) syndrome in 50 (25%); and isolated metabolic changes in 65 (32%). Subjects with morphological alterations displayed a greater cumulative time of exposure to NRTIs and to protease inhibitors than patients with isolated metabolic alterations. Patients with lipoatrophy had had a greater exposure to stavudine.

Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome.

OBJECTIVES: Metabolic syndrome is a cluster of risk factors, such as central obesity, dyslipidemia, glucose intolerance, hypertension, related to insulin resistance. In HIV patients insulin resistance and several metabolic abnormalities of the metabolic syndrome have been described, but few and conflicting studies have investigated the behaviour of blood pressure. The aims of the present study were to evaluate the prevalence of hypertension in a large group of HIV-patients on highly active antiretroviral therapy (HAART) and to investigate the relationship between hypertension, metabolic syndrome and insulin resistance. DESIGN: Case control study. METHODS: We enrolled 287 HIV-positive patients on HAART (mean age 41.1 +/- 7.5 years) and 287 age- and sex-matched controls. Insulin resistance was estimated by the homeostasis model insulin resistance assessment (HOMA) index. Metabolic syndrome was defined according to the European Group for the Study of Insulin Resistance. RESULTS: HIV patients showed a prevalence of subjects with hypertension (34.2 versus 11.9%; P < 0.0001) and metabolic syndrome (33.1 versus 2.4%; P < 0.0001) higher than controls. HOMA was higher in HIV-patients than controls (3.3 +/- 1.2 versus 2.0 +/- 0.9; P < 0.0001). HOMA (3.7 +/- 1.0 versus 3.1 +/- 1.2; P < 0.001) and the prevalence of subjects with the metabolic syndrome (64.3 versus 16.9%; P < 0.0001) were greater in HIV-patients with than in those without hypertension. Multiple logistic regression analysis showed that family history of hypertension (odds ratio [(OR): 8.73; 95% confidence interval (CI): 4.31-17.70; P < 0.0001], metabolic syndrome (OR: 6.79; 95% CI: 3.27-14.10; P < 0.0001), lipodystrophy (OR: 4.80; 95% CI: 2.43-9.85; P < 0.0001) and HOMA (OR: 4.13; 95% CI: 1.14-14.91; P < 0.05) were predictors of hypertension in HIV-patients. CONCLUSIONS: The present study shows that hypertension is frequent in HIV patients on HAART and that hypertension appears to be linked to insulin resistance; in particular, hypertension seems to be a part of the metabolic syndrome.

Clinical experiences with interferon as monotherapy or in combination with ribavirin in patients co-infected with HIV and HCV.

Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.

Host factors affecting the outcome of treatment of hepatitis C.

The development of peginterferon and ribavirin combination therapy has significantly improved the sustained virologic response (SVR) rates in patients with chronic hepatitis C. However, poor patient adherence to therapy negatively influences drug levels and drug exposure, often preventing the development of an inhibitory drug level. To optimize patient adherence, the clinician must recognize factors predicting low adherence and negotiate a treatment plan that the patient understands and to which he or she commits. If adverse effects become intolerable, continuing patients on a reduced dose rather than withdrawing treatment seems to confer considerable advantage in preserving the chance for attaining an SVR. Results of a head-to-head comparison have demonstrated the possibility that, in cases of dose reduction, levels of peginterferon alfa-2a could remain above the limit of detection, whereas those of peginterferon alfa-2b might not.

Fast relapse and high drop out rate of 48 weeks daily interferon monotherapy in HIV-infected patients with chronic hepatitis C.

BACKGROUND: The standard of care for HCV Hepatitis is the combination of interferon (IFN) plus Ribavirin. In HIV patients the use of this combination therapy may induce drug interactions, and reduces the adherence to HAART. The aim of this study is to evaluate safety and efficacy of a 48 weeks daily dose IFN schedule. METHODS: We evaluated 50 coinfected patients; alpha IFN 2a was administered at a dose of 3 MU daily. The baseline values were the following : CD4+ 515 cells/mmc (mean); HIV-RNA <50 copies/ml in all patients; HCV-RNA 28, 3 x 106 copies/ml. RESULTS: At 48 weeks, 10 patients (20%) achieved a biochemical and virological response according to an intention to treat analysis.Twenty four patients (48%) underwent a drop-out mainly by side effects related to overlapping toxicity of interferon and antiretroviral therapy. All the patients, who responded to the treatment, showed a fast relapse one month after the end of treatment. CONCLUSION: Although our results demonstrated a very poor outcome and a bad tolerance to interferon monotherapy, this approach should not be dropped out, mainly in patients at high risk for side effects and in those with cirrhosis who do not tolerate or are at increased risk for the use of ribavirin.

Controlled attenuation parameter for evaluating liver steatosis in chronic viral hepatitis.

AIM: To assess the performance of controlled attenuation parameter (CAP) in patients with chronic viral hepatitis. METHODS: CAP is a new technique that measures the attenuation in the liver of an ultrasound beam, which is directly related to lipid accumulation. Consecutive patients undergoing liver biopsy for chronic viral hepatitis were studied using the M probe of FibroScan device (Echosens, Paris, France). The device estimates liver steatosis in decibel per meter (dB/m). An expert operator performed all measurements. Steatosis was graded according to Kleiner's classification. Pearson or Spearman rank coefficient was used to test correlation between two study variables. Linear regression was used for multivariate model to assess the association between CAP and other variables. Receiver operating characteristic curve analysis was performed to calculate area under the curve (AUROC) for S0 vs S1-S3 and S0-S1 vs S2-S3. RESULTS: 115 subjects (85 males and 30 females) were prospectively studied. The mean values of CAP were 227.1 ± 43.1 for S0; 254.6 ± 38.9 for S1; 297.8 ± 49.4 dB/m for S2-S3. In univariate analysis CAP showed a significant correlation with age, body mass index (BMI), degree of steatosis, and cholesterol. Multivariate regression analysis confirmed the correlation with the degree of steatosis [coefficient, 1.2 (0.60-1.83); P < 10(-5)] and BMI [coefficient, 4.1 (0.5-7.8); P = 0.03] but not with all other variables. Optimal cutoff values for S ≥ 1 and S ≥ 2 were 219 dB/m [AUROC, 0.76 (0.67-0.84); sensitivity, 91.1% (78.8-97.5); specificity, 51.6% (38.7-64.2); positive predictive value, 56.9% (44.7-68.6); negative predictive value, 89.2% (74.3-97.0); positive likelihood ratio, 1.88 (1.4-2.5); negative likelihood ratio, 0.17 (0.07-0.5)] and 296 dB/m [AUROC, 0.82 (0.74-0.89); sensitivity, 60.0% (32.3-83.7); specificity, 91.5% (83.9-96.3); positive predictive value, 52.9% (27.8-77.0); negative predictive value, 93.5% (86.3-97.6); positive likelihood ratio, 7.05 (3.2-15.4); negative likelihood ratio, 0.44 (0.2-0.8)], respectively. CONCLUSION: Controlled attenuation parameter could be a useful tool in the clinical management of patients with chronic viral hepatitis for detecting liver steatosis.

Point shear wave elastography method for assessing liver stiffness.

AIM: To estimate the validity of the point shear-wave elastography method by evaluating its reproducibility and accuracy for assessing liver stiffness. METHODS: This was a single-center, cross-sectional study. Consecutive patients with chronic viral hepatitis scheduled for liver biopsy (LB) (Group 1) and healthy volunteers (Group 2) were studied. In each subject 10 consecutive point shear-wave elastography (PSWE) measurements were performed using the iU22 ultrasound system (Philips Medical Systems, Bothell, WA, United States). Patients in Group 1 underwent PSWE, transient elastography (TE) using FibroScan (Echosens, Paris, France) and ultrasound-assisted LB. For the assessment of PSWE reproducibility two expert raters (rater 1 and rater 2) independently performed the examinations. The performance of PSWE was compared to that of TE using LB as a reference standard. Fibrosis was staged according to the METAVIR scoring system. Receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating characteristic curve (AUC) for F ≥ 2, F ≥ 3 and F = 4. The intraobserver and interobserver reproducibility of PSWE were assessed by calculating Lin's concordance correlation coefficient. RESULTS: To assess the performance of PSWE, 134 consecutive patients in Group 1 were studied. The median values of PSWE and TE (in kilopascals) were 4.7 (IQR = 3.8-5.4) and 5.5 (IQR = 4.7-6.5), respectively, in patients at the F0-F1 stage and 3.5 (IQR = 3.2-4.0) and 4.4 (IQR = 3.5-4.9), respectively, in the healthy volunteers in Group 2 (P < 10(-5)). In the univariate analysis, the PSWE and TE values showed a high correlation with the fibrosis stage; low correlations with the degree of necroinflammation, aspartate aminotransferase and gamma-glutamyl transferase (GGT); and a moderate negative correlation with the platelet count. A multiple regression analysis confirmed the correlations of both PSWE and TE with fibrosis stage and GGT but not with any other variables. The following AUC values were found: 0.80 (0.71-0.87) for PSWE and 0.82 (0.73-0.89) for TE (P = 0.42); 0.88 (0.80-0.94) for PSWE and 0.95 (0.88-0.98) for TE (P = 0.06); and 0.95 (0.89-0.99) for PSWE and 0.92 (0.85-0.97) for TE (P = 0.30) for F ≥ 2, F ≥ 3 and F = 4, respectively. To assess PSWE reproducibility, 116 subjects were studied, including 47 consecutive patients scheduled for LB (Group 1) and 69 consecutive healthy volunteers (Group 2). The intraobserver agreement ranged from 0.83 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 1 and from 0.84 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 2. The interobserver agreement yielded values from 0.83 (95%CI: 0.78-0.88) to 0.93 (95%CI: 0.91-0.95). CONCLUSION: PSWE is a reproducible method for assessing liver stiffness, and it compares with TE. Compared with patients with nonsignificant fibrosis, healthy volunteers showed significantly lower values.