Åsa Alsiö

Cerebrovascular Complications in Patients with Left-Sided Infective Endocarditis Are Common: A Prospective Study Using Magnetic Resonance Imaging and Neurochemical Brain Damage Markers

Background. @nbsp; Cerebrovascular complications (CVCs) have remained a major therapeutic and prognostic challenge associated with infective endocarditis, and definite risk factors have not been fully elucidated. This prospective study was designed to the evaluate the total incidence of CVC associated with infective endocarditis and major risk factors. Methods. @nbsp; During 2 study periods, from June 1998 through April 2001 and from September 2002 through January 2005, patients were prospectively enrolled in the study regardless of neurological symptoms. Study patients underwent neurological examinations and magnetic resonance imaging of the brain, and cerebrospinal fluid analyses of inflammatory and neurochemical markers of brain damage (neurofilament protein and glial fibrillary acidic protein) were performed. Results. @nbsp; Sixty patients who experienced episodes of left-sided infective endocarditis were evaluated; 35% of these patients experienced a symptomatic CVC. Silent cerebral complications were detected in another 30% of the patients, and the total CVC rate was 65% (95% confidence interval, 58%-72%). Five percent of patients experienced their first neurological symptom after the initiation of antibiotic treatment without prior surgery. No new symptomatic CVCs were detected after 10 days of antibiotic treatment. No neurological deterioration was observed after surgery in patients who were established to have a symptomatic CVC preoperatively. A larger heart valvular vegetation size was a risk factor for both symptomatic and silent CVCs; Staphylococcus aureus etiology conferred a higher risk for symptomatic cerebral complication only. Conclusions. @nbsp; The use of sensitive methods of detection indicates that the incidence of CVC associated with infective endocarditis is high, but the risk for neurological deterioration during cardiac surgery after a CVC is lower than previously assumed. The major mechanism behind cerebral complications associated with infective endocarditis is cerebral embolization, although the dominant neurological symptoms vary considerably.

Randomized comparison of 12 or 24 weeks of peginterferon α‐2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection

Previous trials investigating the efficacy of treatment durations shorter than the standard of 24 weeks for chronic hepatitis C virus (HCV) genotype 2/3 infections have yielded discordant results. The aims of this investigator‐initiated phase III study were to compare the efficacy of 12 or 24 weeks of treatment and to identify patients suitable for short‐term therapy. Three hundred eighty‐two genotype 2/3–infected patients [intention‐to‐treat (ITT) population] at 31 centers in Denmark, Finland, Norway, and Sweden were randomized to 12 or 24 weeks of peginterferon α‐2a (180 μg/week) plus ribavirin (800 mg/day). Twelve weeks of therapy was inferior to 24 weeks in the ITT population (sustained viral response [SVR] rates: 59% versus 78%, P < 0.0001) and in the subgroups of patients infected with genotype 2 (56% versus 82%, P = 0.006) or 3 (58% versus 78%, P = 0.0015). These differences were observed regardless of the fibrosis stage. Age and HCV‐RNA levels on days 7 and 29 were independent predictors of SVR. Short‐term treatment was useful in patients < 40 years old, especially if HCV‐RNA was undetectable on day 29, and also in patients ≥ 40 years old, provided that HCV‐RNA was below 1000 IU/mL on day 7 in addition to being undetectable on day 29. If neither of these two criteria were met for patients ≥ 40 years old, 24 weeks of therapy was superior (P < 0.0001). Conclusion: Peginterferon/ribavirin treatment for 12 weeks in HCV genotype 2/3 infection is overall inferior to 24 weeks of treatment but may be useful in some patients with a rapid initial clearance of virus. (HEPATOLOGY 2008.)

Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C†

High systemic levels of interferon‐gamma‐inducible protein 10 kDa (IP‐10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP‐10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP‐10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO‐HCV). Low levels of plasma or intrahepatic IP‐10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.0001 and P = 0.002, respectively) as well as when patients were grouped as genotype 1 or 4 (P = 0.0008 and P = 0.01) and 2 or 3 (P = 0.002, and P = 0.02). Low plasma levels of IP‐10 also were predictive of the absolute reduction of HCV RNA (P < 0.0001) and the maximum reduction of HCV RNA in the first 4 days of treatment (P < 0.0001) as well as sustained virological response (genotype 1/4; P < 0.0001). To corroborate the relationship between early viral decline and IP‐10, pretreatment plasma samples from an independent phase IV trial for HCV genotypes 2/3 (NORDynamIC trial; n = 382) were analyzed. The results confirmed an association between IP‐10 and the immediate reduction of HCV RNA in response to therapy (P = 0.006). In contrast, pretreatment levels of IP‐10 in liver or in plasma did not affect the decline of HCV RNA between days 8 and 29, i.e., the second‐phase decline, or later time points in any of these cohorts. Conclusion: In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP‐10 predict a favorable first‐phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV. (HEPATOLOGY 2010.)

Impact of IL28B-Related Single Nucleotide Polymorphisms on Liver Histopathology in Chronic Hepatitis C Genotype 2 and 3

Background and Aims Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory. Methods Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology. Results IL28B CCrs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CCrs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients. Conclusion This study shows that the CCrs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.

A non-invasive fibrosis score predicts treatment outcome in chronic hepatitis C virus infection

Objective. The results of a previous study suggest that an index calculated according to the formula (normalized ASAT×PK-INR)×100/thrombocyte count (×109/L; GUCI) may reflect liver fibrosis in patients with chronic hepatitis C virus (HCV) infection. The aims of the present study were (i) to validate the association between the Göteborg University Cirrhosis Index (GUCI) score and liver fibrosis and (ii) to evaluate the utility of this index in predicting the outcome of antiviral treatment. Material and methods. A total of 269 patients with chronic HCV infection, stratified according to HCV genotype (1/4 versus 2/3) participated in a phase III trial using pegylated interferon α-2a and ribavirin (DITTO study). Retrospective analyses of the baseline GUCI scores and assessments of pretreatment liver biopsies using the Ishak protocol were performed. Cut-off GUCI scores were calculated to distinguish patients with a high or low probability of sustained viral response (SVR). Results. Striking associations between GUCI and Ishak fibrosis stages (stages 0–2 versus stages 3–4, p=0.0002, stages 3–4 versus stages 5–6, p=0.002) were observed. In patients with genotype 1 or 4, a GUCI score below 0.33 was associated with a rapid viral response to antiviral treatment and an SVR rate of 80%. Ninety-two percent of patients (92/101) with a SVR had a pretreatment GUCI score below 1.11. Conclusions. Our results suggest that the GUCI score appropriately reflects the stage of liver fibrosis in HCV-infected patients, and predicts initial viral kinetics as well as treatment outcome in patients infected with HCV genotype 1 or 4.

Ribavirin plasma concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C virus genotype 2/3 infection

Summary.  In hepatitis C virus (HCV) genotype 1 infection, the likelihood of obtaining sustained virological response (SVR) is associated with higher ribavirin exposure. Such an association has not been demonstrated for HCV genotype 2/3 infection, where a fixed 800 mg daily dosing of ribavirin is generally recommended. The primary aim of this study was to investigate the correlation between ribavirin concentration at day 29 and therapeutic response in patients with HCV genotype 2/3 infection. A total of 382 patients were randomized to 12 or 24 weeks of treatment with pegylated interferon‐alfa 2a 180 μg weekly and 800 mg ribavirin daily. Trough plasma concentration of ribavirin was measured at day 29 and week 12 and the primary outcome was SVR (HCV‐RNA undetectable 24 weeks after treatment). Of the 382 patients, 355 had a ribavirin concentration available at day 29. SVR was 84% among patients with a ribavirin concentration ≥2 mg/L at day 29 compared to 66% in those with concentrations <2 mg/L (P = 0.002). The corresponding figures in the 12‐week treatment group were 74% and 57% (P = 0.12), and in the 24‐week treatment group 91% and 75% (P = 0.02), respectively. In a multivariate analysis, ribavirin concentration at day 29 was an independent predictor of SVR (P = 0.002). In conclusion, a higher plasma ribavirin concentration is associated with an increased likelihood of achieving SVR in HCV genotype 2/3 infection. Individualization of ribavirin dosing may be helpful in improving outcome, especially in the presence of unfavourable baseline characteristics. This, however, requires evaluation in a prospective trial.

Impact of obesity on the bioavailability of peginterferon-α2a and ribavirin and treatment outcome for chronic hepatitis c genotype 2 or 3

Background and Aims Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear. Methods This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC). Results Patients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140). Conclusions Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.

Weight‐adjusted dosing of ribavirin and importance of hepatitis C virus RNA below 1000 IU/mL by day 7 in short‐term peginterferon therapy for chronic genotype 2/3 hepatitis C virus infection

Dalgard and Mangia address an important issue in the treatment of infections with hepatitis C virus (HCV) genotype 2/3, that is, the putative benefit of adjusting the ribavirin dose for weight rather than, as in our NORDynamIC trial, using a fixed dose. The authors specifically point to a higher relapse rate in patients receiving short-term pegylated interferon (peg-IFN) and ribavirin in the NORDynamIC trial than that observed in their own studies.1-3 These divergent relapse rates may reflect a superiority of weight-adjusted dosing of ribavirin, but may also be explained by differences in demographic characteristics of participating patients. For example, 53% of our patients had bridging fibrosis or cirrhosis, compared to 18% in the study by Mangia et al.,3 and 23% in the pilot study by Dalgard et al.1; in the North-C trial, 17% of patients had an aspartate aminotransferase-to-platelet ratio index score 2, indicating significant fibrosis.2 In support of weight-adjusted ribavirin dosing, as proposed by Dalgard et al., the patients in the NORDynamIC trial who achieved sustained virologic response (SVR) after 24 weeks of therapy had a significantly lower body weight than patients not achieving SVR in the per protocol analysis (mean 75.4 kg versus 84.0 kg, P 0.016, MannWhitney U-test), and a similar albeit nonsignificant trend was observed in patients treated for 12 weeks (78.6 kg versus 83.2 kg, P 0.11). On the other hand, the larger prospectively randomized trial by Hadziyannis et al. noted no such significant differences between 800 mg and standard weight-based dosing (1000 mg or 1200 mg) of ribavirin for patients infected with genotype 2/3 who were treated for 24 or 48 weeks.4 It is conceivable that weight adjustment of the ribavirin dose may be preferable in short-term therapy for genotype 2/3 infection. However, it is of note that in studies utilizing weight adjustment as well as fixed dosing of the ribavirin, patients achieving rapid virologic response had consistently higher SVR rates and lower relapse rates following standard 24 weeks of therapy compared to patients who had 12-16 weeks of therapy.2,5,6 We wish to point out, however, that the NORDynamIC trial identified patients in whom short-term treatment appeared to be acceptably efficacious, that is, the group of patients infected with genotype 2/3 with HCV RNA below 1000 IU/mL already by day 7 (that is, immediately prior to the second dose of pegIFN). In these patients (which constituted 30% of the intention-to-treat population), 12 weeks of combination therapy using a fixed dose of 800 mg ribavirin daily yielded SVR rates of 92% and 90% in the intention-to-treat analysis in the 12-week and 24-week arms, respectively, and in the per protocol analysis, the SVR rates were 97% and 98% (Fig. 1). Shortterm treatment thus appears to be suitable as a response-guided therapy for patients infected with genotype 2/3 with a very rapid virologic response, especially if they are adherent to combination therapy.

Short interferon and ribavirin treatment for HCV genotype 2 or 3 infection: NORDynamIC trial and real-life experience

Abstract Objective: Interferon-free therapy for hepatitis C virus (HCV) infection is costly, and therefore patients with advanced fibrosis are prioritized. Although coupled with considerable side effects, a large proportion of genotype 2/3 infected patients achieve a sustained virological response (SVR) following interferon-based therapy. The present study evaluates experimental clinical trial and verifying real-life data with the aim of identifying patients with a high likelihood of favorable outcome following short interferon-based treatment. Material and methods: The impact of established response predictors, e.g. age, ITPA and IL28B genetic variants, IP-10, liver histopathology and early viral kinetics on outcome was evaluated among HCV genotype 2/3 infected patients enrolled in the NORDynamIC trial. Similarly outcome was evaluated among Finnish and Swedish real-life genotype 2/3 infected patients treated for 12–16 weeks in accordance with national guidelines. Results: In the NORDynamIC trial, age <40 years or achieving HCV RNA <1000 IU/mL day 7 were highly predictive of favorable outcome following 12 weeks therapy. Among 255 Finnish real-life patients below the age of 40 years treated for 12 weeks with interferon and ribavirin, 87% of HCV genotype 2 and 79% of genotype 3 infected patients achieved SVR, and among 117 Swedish real-life patients treated for 12–16 weeks, 97% of HCV genotype 2 and 94% of genotype 3 infected achieved SVR. Conclusions: Short interferon-based therapy offers a high likelihood of achieving SVR for selected HCV genotype 2/3 infected patients, and is an acceptable option given that a thorough discussion of the side effects is provided prior to initiation.

Is HCV RNA analysis at day 7 cost-effective in deciding the duration of therapy in chronic HCV genotype 2/3 infection?

To the Editor: The recent study by Sarrazin et al. [1] reported results from a reanalysis of stored sera from two large multicenter randomized trials [2,3], in HCV infected patients treated with peginterferon alfa-2a plus ribavirin. The authors quantified HCV RNA using COBAS Ampliprep/COBAS TaqMan (CAP–CTM), a sensitive realtime PCR-based assay with a limit of detection of 615 IU/ml. Among genotype 2/3 infected patients achieving a rapid virologic response (RVR; defined as HCV RNA <15 IU/ml after 4 weeks of therapy), a sustained viral response (SVR) rate of 83% was noted for patients treated for 16 weeks and 91% for those treated for 24 weeks. These SVR rates were observed in both study arms even when using a stricter definition of undetectable HCV RNA (CAP–CTM). However, when the analysis was limited to patients with a baseline viral load below 800,000 IU/ml, i.e. a third of the patients included, the authors found no statistically significant difference in SVR rates between patients treated for 16 or 24weeks irrespective of the cut-off used to define RVR. In another recently reported trial with HCV genotype 2/3 infected patients (NORDynamIC; n = 382) treated with peginterferon alfa-2a weekly plus 800 mg ribavirin daily for 12 or