Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes.

BACKGROUND AND AIMS: Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have, however, been mainly from tertiary care centers, with risk for referral bias toward patients with worse outcomes. Furthermore, the impact of HDV viremia per se on liver-related outcomes is not really known outside the human immunodeficiency virus co-infection setting. We have therefore evaluated the long-term impact of HDV viremia on liver-related outcomes in a nationwide cohort of patients with hepatitis B and D co-infection, cared for at secondary care centers in Sweden. APPROACH AND RESULTS: In total, 337 patients with anti-HDV positivity, including 233 patients with HDV RNA viremia and 91 without HDV viremia at baseline, were retrospectively studied, with a mean follow-up of 6.5 years (range, 0.5-33.1). The long-term risks for liver-related events (i.e., hepatocellular carcinoma [HCC], hepatic decompensation, or liver-related death/transplantation) were assessed, using Cox regression analysis. The risk for liver-related events and HCC was 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia compared with those without viremia, although the latter was not statistically significant. Among patients with HDV viremia with no baseline cirrhosis, the cumulative risk of being free of liver cirrhosis or liver-related events was 81.9% and 64.0% after 5 and 10 years of follow-up, respectively. This corresponds to an incidence rate of 0.04 cases per person-year. CONCLUSIONS: HDV RNA viremia is associated with a 3.8-fold higher risk for liver-related outcomes. The prognosis was rather poor for patients with HDV viremia without cirrhosis at baseline, but it was nevertheless more benign than previous estimates from tertiary centers. Our findings may be of importance when making decisions about treatment and evaluating potential outcomes of upcoming antivirals against HDV.

Plasma FABP4 is associated with liver disease recovery during treatment-induced clearance of chronic HCV infection.

Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.

High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1-Infected Patients.

BACKGROUND: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration-monitored ribavirin. METHODS: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of >15 µmol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. RESULTS: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P < 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. CONCLUSIONS: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given.

A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis.

BACKGROUND: The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. METHODS: These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. RESULTS: Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. CONCLUSIONS: The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Comparison of two infusion rates of antithrombin concentrate in cardiopulmonary bypass surgery.

BACKGROUND: Antithrombin concentrate (AT) is used to treat heparin resistance (HR) in cardiac surgery. It is usually given slowly due to the fear of anaphylaxis. This may delay cardiac catheterisation and the start of cardiopulmonary bypass (CPB). HR is often defined as the failure to reach or maintain a target activated clotting time (ACT) despite a standard dose of heparin. It is not generally possible to predict which patients will display HR, although there are known risk factors. Routine early administration of AT before heparinisation is probably not cost-effective. Infusing AT relatively quickly after demonstrating HR may be more cost-effective, while not delaying surgery. The aim of this study is to investigate the safety and side effects of a faster infusion of AT. METHODS: Forty patients undergoing elective heart surgery were included and randomised to two groups in a double-blind fashion. Each group received 1000 IU of AT intravenously (IV). One group received a slow infusion (100 IU/min) before full-dose heparinisation. The other group received a fast infusion (250 IU/min). Haemodynamic and respiratory data were recorded. Any adverse effects were noted. Thrombin-antithrombin, anti-Xa and antithrombin levels in plasma were measured. RESULTS: No anaphylaxis occurred in either group. No differences were found regarding haemodynamics, respiration or laboratory results. Two patients experienced major haemorrhage and recovered; there were two deaths, thought to be unrelated to the study drugs. CONCLUSION: AT can be infused at a rate of 250 IU/min. This is faster than the current recommendation of 100 IU/min. This rate of infusion allows restricting AT infusion to those patients who display HR, without delaying surgery. Optimal anticoagulant therapy for CPB probably includes point-of-care measurement of ACT and plasma AT and small, but rapid, infusions of AT in heparin-resistant patients.

Pegylated interferon and ribavirin combination therapy for chronic hepatitis C virus infection in patients with Child-Pugh Class A liver cirrhosis.

OBJECTIVE: Pegylated interferon (peg-IFN) and ribavirin (RBV) treatment is less effective in patients with hepatitis C virus (HCV) and liver cirrhosis than in non-cirrhotic patients. Many patients with advanced liver disease have been excluded from the pivotal randomized controlled studies. The aim of this study was to investigate the efficacy and tolerability of combination therapy in unselected patients with Child-Pugh Class A liver cirrhosis at a Swedish university clinic. MATERIAL AND METHODS: The virologic response and adverse events were retrospectively analyzed in 104 patients with HCV-associated Child-Pugh Class A liver cirrhosis who had been treated with peg-IFN and RBV. RESULTS: Overall sustained virologic response (SVR) was achieved in 13% genotype 1-, 60% genotype 2-, and 31% genotype 3-infected patients. In treatment-naive patients, the corresponding rates were 13%, 82%, and 38%, respectively. In 46% of patients, treatment was discontinued prematurely owing to lack of virologic response in the majority. CONCLUSIONS: SVR rates found in our study, in particular for genotype 1 patients (13%), were lower than those generally found in randomized controlled studies. For cirrhotic patients, new treatment alternatives are urgently needed to improve treatment outcome.

Rapid viral response and treatment outcome in genotype 2 and 3 chronic hepatitis C: comparison between two HCV RNA quantitation methods.

Fifty consecutive patients with genotype 2 or 3 chronic hepatitis C were treated with peg-IFN alfa-2a 135 microg weekly and ribavirin (11 mg/kg body weight) daily during 24 weeks. Rapid viral response treatment week 4, end-of-treatment response, and sustained viral response were analyzed by two different HCV RNA quantitation methods, the Cobas Amplicor Monitor test and the TaqMan test with a sensitivity of 600 and 15 IU/ml, respectively. The TaqMan test differentiated patients with rapid viral response finally achieving sustained viral response better. Hence, patients with and without rapid viral response as tested by the TaqMan test finally achieved sustained viral response in 97% (32/33) versus in 75% (12/16), P < 0.017. The corresponding figures for the Cobas Amplicor test was 91% (41/45) versus (80%) 4/5 a non-significant difference. In conclusion, the more sensitive TaqMan test yielded a lower number of patients with rapid viral response than the less sensitive Amplicor Monitor test, but predicted sustained viral response in a higher percentage of patients with rapid viral response than the Amplicor Monitor test. A rapid viral response meaning HCV RNA levels <15 IU/ml predicted a sustained viral response in 97% of patients with genotype 2 or 3.

Hepatitis C virus RNA levels during initial induction or standard interferon therapy: influence of continued treatment on sustained response.

Hepatitis C virus (HCV) RNA kinetics were studied at baseline weeks 4, 8 and 12 during interferon-alpha (IFN) monotherapy in 65 patients (mean age 39 y, range 19-66 y) with chronic HCV infection. IFN treatment was given either as initial induction (n = 34) or as standard dosing 3 times a week (n = 31). Patients with genotypes 2 and 3 had a significantly steeper decline in HCV RNA levels than patients with genotype 1 at weeks 4, 8 and 12 (p < 0.001 at all points measured). The decline in viral load was more pronounced in patients with induction therapy than with standard therapy at weeks 4, 8 and 12 (p < 0.02, 0.054 and 0.01, respectively). Patients with a sustained viral response had a 3-log decline in viral levels at week 4, with few exceptions. Two patients with non-response at week 12 (1 each with genotype 1 and non-1) responded after supplementation with ribavirin.