Real-world experience for the outcomes and costs of treating hepatitis C patients: Results from the German Hepatitis C-Registry (DHC-R).

BACKGROUND & AIMS: With long-term consequences like the development of liver cirrhosis and hepatocellular carcinoma, chronic hepatitis C virus (HCV) infection is associated with a significant health burden. Information on HCV treatment outcomes and costs in routine care is still rare, especially for subgroups. The aim of this study was to analyse the treatment outcomes and costs of subgroups in routine care and to compare them over time with previous analyses. METHODS: Data were derived from a noninterventional study including a subset of 10298 patients receiving DAAs with genotypes 1 and 3. Sociodemographic, clinical parameters and costs were collected using a web-based data recording system. The total sample was subdivided according to treatment regimen, cirrhosis status as well as present HIV infection and opioid substitution treatment (OST). RESULTS: 95% of all patients achieved SVR. Currently used DAA showed higher SVR-rates and less adverse events (AE) compared to former treatments. Concerning subgroups, cirrhotic patients, HIV-coinfected patients and OST patients showed lower but still high SVR-rates. In comparison, cirrhotic had considerably longer treatment duration and more frequent (serious) AE. Overall, average treatment costs were €48470 and costs per SVR were €51129; for currently used DAAs costs amounted to €30330 and costs per SVR to €31692. After the end of treatment, physical health is similar to the general population in all patients except cirrhotic. Mental health remains far behind in all subgroups, even for currently used DAA. CONCLUSIONS: Over time, some relevant factors developed positively (SVR-rates, costs, treatment duration, adverse events, health-related quality of life (HRQoL)). Further research on HRQoL, especially on mental health, is necessary to evaluate the differences between subgroups and HRQoL over time and to identify influencing factors.

Alcohol and Cannabis Consumption Does Not Diminish Cure Rates in a Real-World Cohort of Chronic Hepatitis C Virus Infected Patients on Opioid Substitution Therapy-Data From the German Hepatitis C-Registry (DHC-R).

BACKGROUND: The importance of alcohol and cannabis consumption for the effectiveness of treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) in people on opioid substitution therapy (OST) has not been investigated in detail. METHODS: We investigated sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST (n = 739) and non-OST patients (n = 7008) in the German Hepatitis C-Registry (Deutsches Hepatitis C-Register, DHC-R), which is a national multicenter prospective non-interventional real-world registry. Non-OST patients comprised patients with former/current drug use (non-OST/DU; n = 1500) and patients never consuming drugs (non-OST/NDU; n = 5508). FINDINGS: SVR 12/24 rates (intention to treat [ITT]) in patients consuming no or less than 30 g/day (women) or 40 g/day (men) were significantly higher in non-OST/NDU (range 91%-92%) vs OST patients (range 83%-86%), mainly due to significantly higher LTFU rates in OST (range 11%-12%) compared with non-OST/NDU (range 2%-3%). In non-OST/NDU with high alcohol consumption of more than 30/40 g/day, SVR 12/24 rates (ITT) were lower (85%) but did not differ to OST (85%) with high alcohol consumption. No significant differences could be seen for SVR 12/24 in per-protocol (PP) analysis independent of alcohol consumption or amount of alcohol intake. Cannabis use did not significantly influence SVR 12/24 in ITT or PP or LTFU. CONCLUSIONS: High SVR rates could be achieved in both OST and non-OST patients irrespective of alcohol or cannabis consumption. However, LTFU is more likely in patients with current or former drug use than in patients without drug history and in patients with high alcohol consumption but occurred mainly after end of antiviral treatment (EOT), leaving a high chance for HCV elimination in these patients.

[4 years of direct-acting antivirals (DAAs) in the German Hepatitis C-Registry (DHC-R)]. / Deutsches Hepatitis C-Register (DHC-R) ­ eine Zwischenbilanz 4 Jahre nach Zulassung direkt antiviraler Substanzen (DAAs).

BACKGROUND: More than 250 000 patients suffer from chronic hepatitis C in Germany. Several potent, direct-acting antiviral drugs have been approved since 2014. The aim of the German Hepatitis C-Registry (DHC-R) is to describe the epidemiology and patient care of hepatitis C and to investigate the efficacy and safety of new treatment options in real-world settings. METHODS: The DHC-R is a prospective multicenter non-interventional registry study that includes 327 centers throughout Germany. All approved treatment options have been documented. The current analysis differentiated 4 phases: 2/2014 - 12/2014, 1/2015 - 12/2015, 1/2016 - 7/2017 and 8/2017 - 7/2018. FINDINGS: Between February 2014 and July 2018, 12 170 patients were included in the registry (61.3 % male), and antiviral treatment was initiated in 11 268. The mean age declined from 52.3 years (phase 1) to 49.3 years (phase 4), while the proportion of patients with previous or ongoing drug abuse increased (26.3 % to 43.1 %). In 2014, 35.1 % of treated patients had liver cirrhosis, which declined to 16.5 % in phase 4. The HCV genotype distribution showed marked fluctuations, with most recent increases in HCV genotype 3 (30 % in phase 4). Per-protocol sustained virological response rates increased from 92.8 % in 2014 to 94.4 % in 2017/18 with excellent tolerability. SUMMARY: The DHC-R mirrors patient care of chronic hepatitis in the real-world setting in Germany and provides insights into epidemiology developments. It also confirms the high efficacy and safety of novel treatment options.

Effectiveness and Safety of Direct-Acting Antiviral Combination Therapies for Treatment of Hepatitis C Virus in Elderly Patients: Results from the German Hepatitis C Registry.

BACKGROUND: With the aging of the hepatitis C virus (HCV)-infected patient cohort and the availability of highly effective and tolerable treatment regimens, an increasing number of elderly patients are now eligible for HCV therapy. This study investigated clinical and epidemiologic characteristics of elderly HCV-infected patients as well as the effectiveness and safety of available therapies. METHODS: Patients were enrolled into the German Hepatitis C Registry (DHC-R), a prospective, multicenter, real-world cohort study. Patients were treated at the discretion of the physician, and data were collected by a web-based system. RESULTS: Of 7133 patients who initiated treatment, 686 (9.6%) were > 70 years of age. In patients > 70 years, intent-to-treat (ITT) SVR12 was 92.6% (514/555) compared to 90.7% (4521/4985) in patients ≤ 70 years of age. Overall, adverse events (AEs) were reported in 374 (54.5%) and 3435 patients (53.3%) > 70 or ≤ 70 years of age; 7.6% (52) and 3.6% (235) in the respective age groups had a serious AE. Twenty-two (3.2%) and 62 (1.0%) of the patients > 70 or ≤ 70 years discontinued treatment due to AEs. Death was reported in 34 patients, of whom eight were > 70 years of age. Frequent comorbidities in patients > 70 years of age were cardiac disease, renal disease and diabetes. Psychiatric disorders, substance abuse and viral co-infection were more frequent in younger patients. CONCLUSION: Direct-acting antiviral therapies were well tolerated in patients older than 70 years. SVR12 rates in the elderly patient group were similar to those observed in younger patients. Differences in the prevalence of comorbidities between age groups warrant individualized attention with respect to drug-drug interactions and therapy adherence. The study was registered in the German Clinical Trials Register, DRKS-ID: DRKS00009717.

Treatment of hepatitis C genotype 1 infection in Germany: effectiveness and safety of antiviral treatment in a real-world setting.

BACKGROUND: In pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%. OBJECTIVE: The objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study. METHODS: The German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician. RESULTS: A total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24-1.43); p < 0.001), negatively associated with presence of liver cirrhosis (OR 0.71 (0.56-0.89); p < 0.003) and positively associated with female gender (OR 1.52 (1.21-1.91); p < 0.001). CONCLUSION: Data from this real-world registry show SVR12 rates close to those obtained in clinical studies. Discontinuation rates are low, confirming good tolerance of the regimens and good adherence of patients (Trial registration number DRKS00009717, German Clinical Trials Register, DRKS).

Direct-acting antiviral treatment of chronic HCV-infected patients on opioid substitution therapy: Still a concern in clinical practice?

BACKGROUND AND AIMS: There is limited real-world information on the effectiveness of antiviral treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAA) in people on opioid substitution therapy (OST). This study compared sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST and non-OST patients in the German Hepatitis C-Registry (DHC-R). DESIGN: National multi-centre prospective real-world registry (German Hepatitis C-Registry, DHC-R). Non-OST patients comprised patients with former/current drug use (non-OST/DU) and patients never consuming drugs (non-OST/NDU). SETTING: A total of 254 medical centres in Germany, including 123 centres providing OST. PARTICIPANTS: A total of 7747 chronic HCV patients started DAA therapy (739 OST and 7008 non-OST; 1500 non-OST/DU; 5508 non-OST/NDU) patients. Five hundred and twenty-eight OST and 5582 non-OST patients had completed antiviral therapy and at least one follow-up documentation [intention-to-treat (ITT) population]. MEASUREMENTS: Study outcomes were SVR, proportion of LTFU and safety of treatment. FINDINGS: SVR (ITT) was documented in 85% (450 of 528) OST patients versus 86% (969 of 1126) in non-OST/DU (P = 0.651) and 92% (4113 of 4456) non-OST/NDU (P < 0.001) patients. Independent predictors for SVR (P < 0.01 in multivariate analysis) included HCV genotype non-3 [adjusted odds ratio (aOR) = 1.11; 95% confidence interval (CI) = 1.07-1.15], female sex (aOR = 1.59; CI = 1.30-1.94), platelet counts >90 × 109/l (aOR = 1.51, CI = 1.14-2.01), cirrhosis (aOR = 0.77; CI = 0.62-0.96) and patient group (OST/DI (aOR = 0.58; CI = 0.42-0.78); non-OST/DU (OR: 0.63; CI = 0.50-0.78). In per-protocol analysis (PP), SVR rates were ≥ 94% in all patient groups. In OST the proportion of LTFU was higher (10.2%) than in non-OST/DU (8.5%) and non-OST/NDU (3.2%, P < 0.001) patients. Independent factors for LTFU (P < 0.01) were HCV genotype non-3 (aOR = 0.92; CI = 0.88-0.96), female sex (aOR: 0.7; CI = 0.53-0.92), pre-treatment (aOR = 0.64; CI = 0.50-0.82), OST/DI (aOR = 3.35; CI = 2.35-4.78) and non-OST/DU (aOR = 2.38; CI = 1.80-3.14). CONCLUSIONS: In Germany, direct-acting antiviral treatment of former or current drug users with or without opioid substitution therapy can achieve equally high sustained virological response rates as in patients with no history of drug use.

Outcomes and Costs of Treating Hepatitis C Patients in the Era of First Generation Protease Inhibitors - Results from the PAN Study.

1 OBJECTIVE: Chronic hepatitis C virus infections (HCV) cause a significant public health burden. Introduction of telaprevir (TVR) and boceprevir (BOC) has increased sustained virologic response rates (SVR) in genotype 1 patients but were accompanied by higher treatment costs and more side effects. Aim of the study was to assess outcomes and costs of treating HCV with TVR or BOC in routine care. 2 MATERIAL AND METHODS: Data was obtained from a non-interventional study. This analysis relates on a subset of 1,786 patients for whom resource utilisation was documented. Sociodemografic and clinical parameters as well as resource utilisation were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. 3 RESULTS: Mean age of patients was 49.2 years, 58.6% were male. In treatment-naive patients SVR-rates of 62.2% and 55.7% for TVR and BOC were observed (prior relapser: 68.5% for TVR and 63.5% for BOC; prior non-responder: 45.6% for TVR and 39.1% for BOC). Treatment costs are dominated by costs for pharmaceuticals and range between €39,081 and €53,491. We calculated average costs per SVR of €81,347 (TVR) and €70,163 (BOC) in treatment-naive patients (prior relapser: 78,089 €/SVR for TVR and 82,077 €/SVR for BOC; prior non-responder: 116,509 €/SVR for TVR and 110,156 €/SVR for BOC). Quality of life data showed a considerable decrease during treatment. 4 CONCLUSION: Our study is one of few investigating both, outcomes and costs, of treating HCV in a real-life setting. Data can serve as a reference in the discussion of increasing costs in recently introduced agents.

Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting.

BACKGROUND: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. METHODS: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). RESULTS: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). CONCLUSION: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.

Benefit of Treatment Individualization in Patients with Chronic Hepatitis C Receiving Peginterferon Alfa-2a and Ribavirin in a Large Noninterventional Cohort Study.

BACKGROUND AND AIMS: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes. METHODS: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization. RESULTS: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period. CONCLUSIONS: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.

Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial.

UNLABELLED: Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 µg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00803309.

Treatment of naïve patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.

Noncompliance with guidelines for the treatment of hepatitis C is frequent in daily practice.

PURPOSE: In trials of pegylated interferons (PEG-IFNs), the lack of an early virological response (EVR) was associated with sustained virological response (SVR) rates of only 0-3%. The rates were similarly low when hepatitis C virus (HCV)-RNA was positive at week 24. Treatment guidelines therefore recommend 'stop rules' on the basis of HCV-RNA levels at weeks 12 and 24 of treatment. We analyzed the use of these rules under 'real-life' conditions. PATIENTS AND METHODS: This was a prospective, community-based cohort study involving 467 physicians from institutions throughout Germany, including 4727 treatment-naive genotype-1 patients who received a full course of treatment with PEG-IFN α-2a plus ribavirin between 2003 and 2009. RESULTS: The overall SVR rate was 43.1%. Failure to determine EVR decreased from 20% in 2003-2004 to 10% in 2006-2007. Unexpectedly, treatment was continued in 86.1% of patients without an EVR and in those who had an EVR but were HCV-RNA positive at week 24 (67.5%), resulting in SVR rates of 15.7 and 40.9%, respectively. Between 77.5 and 95.3% of physicians did not follow prescribed recommendations to reduce PEG-IFN or ribavirin in cases of hematological abnormalities. CONCLUSION: Although recommendations to assess EVR and HCV-RNA at week 24 were increasingly observed in daily practice, the corresponding 'stop rules' in nonresponders were neglected. The subsequent SVR was 5-10 times higher than that reported in controlled trials. This may partly be because of the fact that reductions in PEG-IFN or ribavirin dose were not performed despite recommendations. The issue of stop rules will gain even more interest since the first HCV protease inhibitors have been approved. Prolongation of treatment beyond the new stop rules is associated with risks of resistant HCV variants. Thus, the new stop rules are to be observed more strictly when compared with previous therapy with interferons and ribavirin.

Plasma bile acids are not associated with energy metabolism in humans.

Bile acids (BA) have recently been shown to increase energy expenditure in mice, but this concept has not been tested in humans. Therefore, we investigated the relationship between plasma BA levels and energy expenditure in humans. Type 2 diabetic (T2DM) patients (n = 12) and gender, age and BMI-matched healthy controls (n = 12) were studied before and after 8 weeks of treatment with a BA sequestrant. In addition, patients with liver cirrhosis (n = 46) were investigated, since these display elevated plasma BA together with increased energy expenditure. This group was compared to gender-, age- and BMI-matched healthy controls (n = 20). Fasting plasma levels of total BA and individual BA species as well as resting energy expenditure were determined. In response to treatment with the BA sequestrant, plasma deoxycholic acid (DCA) levels decreased in controls (-60%, p < 0.05) and T2DM (-32%, p < 0.05), while chenodeoxycholic acid (CDCA) decreased in controls only (-33%, p < 0.05). Energy expenditure did not differ between T2DM and controls at baseline and, in contrast to plasma BA levels, was unaffected by treatment with the BA sequestrant. Total BA as well as individual BA species did not correlate with energy expenditure at any time throughout the study. Patients with cirrhosis displayed on average an increase in energy expenditure of 18% compared to values predicted by the Harris-Benedict equation, and plasma levels of total BA (up to 12-fold) and individual BA (up to 20-fold) were increased over a wide range. However, neither total nor individual plasma BA levels correlated with energy expenditure. In addition, energy expenditure was identical in patients with a cholestatic versus a non-cholestatic origin of liver disease while plasma total BA levels differed four-fold between the groups. In conclusion, in the various (patho)physiological conditions studied, plasma BA levels were not associated with changes in energy expenditure. Therefore, our data do not support an important role of circulating BA in the control of human energy metabolism.

Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis.

Liver cirrhosis is a catabolic disease associated with a high incidence of insulin resistance and diabetes mellitus. Pre-B cell colony-enhancing factor/ nicotinamide phosphoribosyltransferase/visfatin has been characterized as a novel adipokine with a potential role in glucose metabolism and nicotinamide dinucleotide (NAD) generation. We studied plasma levels and metabolic relevance of visfatin in 19 patients with cirrhosis and 19 body mass index-, age-, and sex-matched controls. In addition, hepatic mRNA expression was assessed by qPCR in livers of seven patients with cirrhosis and four controls. Circulating visfatin was 78% lower in cirrhotics (P < 0.001) and decreased with worsening of the clinical stage of liver disease. Hepatic visfatin secretion decreased with clinical stage (P < 0.05) and reduced liver function (P = 0.01). Consistent with these data, hepatic visfatin mRNA expression was significantly lower in cirrhotic livers (P < 0.05). Circulating visfatin in cirrhosis was correlated with body cell mass (r = 0.72, P < 0.01) as well as with body fat mass (r = 0.53, P < 0.05) but not with plasma glucose, insulin, the degree of insulin resistance, or whole body glucose oxidation rates. Higher visfatin levels were associated with higher hepatic glucose production (r = 0.53, P < 0.05) and also with a higher arterial ketone body ratio (KBR) (r = 0.48, P < 0.05), an indicator of increased hepatic NAD generation. In conclusion, circulating visfatin levels are significantly decreased in liver cirrhosis, presumably attributable to decreased hepatic expression and production. Plasma visfatin in cirrhosis is not associated with insulin resistance but correlates with hepatic glucose production and the arterial KBR, indicating a potential link between the NAD-generating properties of visfatin and metabolism.

Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV.

BACKGROUND/AIMS: The significance of hepatitis A virus (HAV) super-infection in patients with chronic hepatitis C had been a matter of debate. While some studies suggested an incidence of fulminant hepatitis A of up to 35%, this could not be confirmed by others. METHODS: We identified 17 anti-HCV-positive patients with acute hepatitis A from a cohort of 3170 anti-HCV-positive patients recruited at a single center over a period of 12 years. RESULTS: Importantly, none of the anti-HCV-positive patients had a fulminant course of hepatitis A. HCV-RNA was detected by PCR in 84% of the anti-HCV-positive/anti-HAV-IgM-negative patients but only in 65% of anti-HCV-positive patients with acute hepatitis A (p=0.03), indicating suppression of HCV replication during hepatitis A. Previous HAV infection had no effect on HCV replication. After recovery from hepatitis A, an increased HCV replication could be demonstrated for 6 out of 9 patients with serial quantitative HCV-RNA values available while 2 patients remained HCV-RNA negative after clearance of HAV throughout follow-up of at least 2 years. CONCLUSIONS: HAV super-infection is associated with decreased HCV-RNA replication which may lead to recovery from HCV in some individuals. Fulminant hepatitis A is not frequent in patients with chronic hepatitis C recruited at a tertiary referral center.

Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance.

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels (P < 0.001) with hepatic venous resistin being higher than arterial levels (P < 0.001). Circulating resistin was significantly correlated with plasma TNF-alpha levels (r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production (r = -0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies (r = 0.48, P < 0.001) as well as hepatic ketone body production (r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved (P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis.

Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy.

BACKGROUND/AIMS: Up to 50% of patients infected with the hepatitis C virus (HCV) complain of chronic fatigue and difficulties in concentration and memory. The aim of the present study was to seek evidence for the presence of central nervous system involvement in HCV infected patients with only mild liver disease. METHODS: Thirty HCV infected patients with normal liver function, 15 of whom were identified as having mild and 15 moderate to severe fatigue using the fatigue impact scale, underwent neurological and neuropsychological examination, electroencephalography (EEG) and cerebral proton magnetic resonance imaging (MRI) and spectroscopy (MRS). Fifteen healthy volunteers, matched for age and educational attainment, served as controls. RESULTS: In comparison to the healthy controls the patients with HCV infection showed evidence of cognitive impairment, primarily attention and higher executive functions, higher levels of anxiety and depression and impairment of quality of life. In addition they showed a significant decrease of the N-acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS while the EEG was slowed in 25%. In general the deficits were more marked in the patients with moderate rather than mild fatigue. CONCLUSIONS: The data provide evidence of central nervous system involvement in patients with HCV infection.

Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation.

With increasing long-term survival rates after orthotopic liver transplantation (OLT), metabolic alterations complicating the clinical course, such as diabetes mellitus (DM), become increasingly important. Liver cirrhosis is associated with severe alterations in glucose metabolism. However, it is currently unclear whether these changes are reversed by successful OLT. We therefore characterized glucose metabolism in patients with liver cirrhosis and normal fasting glucose levels before OLT (cir), in the clinically stable long-term course after OLT (OLT), and control subjects (con) using oral glucose tolerance tests (cir = 100, OLT = 62, con = 32), euglycemic-hyperinsulinemic clamps (cir = 10, OLT = 27, con = 14), and positron emission tomography (PET) scan analysis with 18F-fluorodeoxyglucose (FDG) as a tracer (cir = 7, OLT = 7, con = 5). Fasting insulin and C-peptide levels were significantly elevated in patients with liver cirrhosis compared with both control subjects (P <.001) and patients after OLT (P <.001). After OLT, insulin was normalized, whereas C-peptide remained elevated (P < 0.01). In the patients with liver cirrhosis, 27% had a normal glucose tolerance, 38% had an impaired glucose tolerance (IGT), and 35% were diabetic. After OLT, 34% had a normal glucose tolerance, 29% an IGT, and 37% were diabetic. Comparison of the same patients before and after OLT demonstrated that IGT or diabetes before OLT was the major risk factor for these conditions after OLT, which was independent of either immunosuppression (cyclosporine vs FK506) or low-dose prednisolone. Total glucose uptake was reduced in patients with liver cirrhosis to less than half the values in control subjects (21.2 +/- 2.8 vs 43.7 +/- 2.4 micromol/kg/minute, respectively, P <.001), whereas patients after OLT showed intermediate values (35.7 +/- 1.4 micromol/kg/minute, P < 0.05 vs con, P < 0.01 vs cir). This difference was caused by a reduction in nonoxidative glucose metabolism in patients with liver cirrhosis compared with control subjects (7.4 +/- 1.9 vs 28.7 +/- 1.8 micromol/kg/minute, respectively, P <.01) and patients after OLT (20.1 +/- 1.4 micromol/kg/minute, P < 0.05 vs con and OLT). In the PET study, skeletal muscle glucose uptake was significantly reduced in patients with liver cirrhosis compared with control subjects (3.5 +/- 0.4 vs 11.8 +/- 2.5 micromol/100g/minute, respectively, P <.05). After OLT, muscle glucose uptake improved compared with patients with liver cirrhosis (5.9 +/- 1.0 micromol/100g/minute, P <.05) but remained significantly lower than in control subjects (P <.05). In conclusion, these results demonstrate that preexisting IGT or diabetes are the major risk factors for IGT and diabetes after OLT. This finding was independent of the immunosuppressive medication. The peripheral insulin resistance in cirrhosis is characterized by a decrease in nonoxidative glucose disposal that is improved, but not normalized, after OLT.

Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics.

Adiponectin is a novel adipocytokine negatively correlated with parameters of the metabolic syndrome, such as body mass index (BMI), body fat mass (BFM), and circulating insulin levels. Furthermore, metabolic actions directly on the liver have been described. The aim of the present study was to characterize circulating adiponectin levels, hepatic turnover, and the association of adiponectin with key parameters of hepatic as well as systemic metabolism in cirrhosis, a catabolic disease. Circulating adiponectin levels and hepatic turnover were investigated in 20 patients with advanced cirrhosis. Hepatic hemodynamics [portal pressure, liver blood flow, hepatic vascular resistance, indocyanine green (ICG) half-life], body composition, resting energy expenditure, hepatic free fatty acids (FFA) and glucose turnover, and circulating levels of hormones (catecholamines, insulin, glucagon) and proinflammatory cytokines (IL-1beta, TNF-alpha, IL-6) were also assessed. Circulating adiponectin increased dependently on the clinical stage in cirrhosis compared with controls (15.2 +/- 1.7 vs. 8.2 +/- 1.1 microg/ml, respectively, P < 0.01), whereas hepatic extraction decreased. Adiponectin was negatively correlated with parameters of hepatic protein synthesis (prothrombin time: r = -0.62, P = 0.003; albumin: r = -0.72, P < 0.001) but not with transaminases or parameters of lipid metabolism. In addition, circulating adiponectin increased with portal pressure (r = 0.67, P = 0.003), hepatic vascular resistance (r = 0.60, P = 0.008), and effective hepatic blood flow (ICG half-life: r = 0.69, P = 0.001). Adiponectin in cirrhosis was not correlated with BMI, BFM, parameters of energy metabolism, insulin levels, hepatic FFA and glucose turnover, and circulating proinflammatory cytokines. These results demonstrate that 1) adiponectin plasma levels in cirrhosis are significantly elevated, 2) the liver is a major source of adiponectin extraction, and 3) adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function and altered hepatic hemodynamics.