H. Van Vlierberghe

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Factors influencing ribavirin-induced hemolysis

BACKGROUND/AIMSnOne of the major side effects of the combination therapy for chronic hepatitis C is ribavirin-induced hemolytic anemia. Little is known about variables influencing this anemia. Our study tried to search for these variables in a large group of patients with hepatitis C treated with the combination therapy.nnnMETHODSnTwo hundred and forty-four patients chronically infected with the hepatitis C virus were treated either with induction treatment (daily dose of interferon) or with a standard treatment (interferon thrice weekly). Both groups received 1,000-1,200 mg of ribavirin from week 4 until the end of the treatment. The drop in hemoglobin level was defined as the difference between the pretreatment hemoglobin level and the hemoglobin level at week 8. Seventeen variables which could possibly influence this drop in hemoglobin level were examined.nnnRESULTSnAfter multivariate analysis, the drop in hemoglobin level was only significant influenced by pretreatment platelet level, treatment and haptoglobin phenotype. The ribavirin dose did not influence the drop in hemoglobin level or the early virological response.nnnCONCLUSIONSnRibavirin-induced hemolysis is influenced by the pretreatment platelet level, the administered amount of alpha-interferon and the haptoglobin phenotype. A careful search for the minimal dose of ribavirin needed in combination treatment is necessary.

The HCV serum proteome: a search for fibrosis protein markers.

Summary.u2002 Liver fibrosis/cirrhosis is a serious health issue in hepatitis C virus (HCV‐) infected patients and is currently diagnosed by the invasive liver biopsy. The aim of this study was to find useful fibrosis markers in HCV‐patients’ sera of different fibrosis degrees (METAVIR F0‐F4) based on proteomics. Serum proteome profiles were created by two‐dimensional gel electrophoresis. Profiles were analysed between different degrees of fibrosis (F0‐F4) and between early (F0F1) and late (F2F3F4) fibrosis by univariate analyses (Pu2003≤u20030.05). Differentially expressed proteins were subsequently identified by mass spectrometry. Mac‐2‐binding protein, α‐2‐macroglobulin and hemopexin were increased in F4 opposite F0/F1. A‐1‐antitrypsin, leucine‐rich α‐2‐glycoprotein and fetuin‐A were decreased in F4 opposite F0/F1. Late fibrosis was characterized by an increase in Mac‐2‐binding protein, α‐2‐macroglobulin and α‐1B‐glycoprotein expression and a decrease in haptoglobin expression. Mac‐2‐binding protein expression was confirmed by dot blot assay and enzyme‐linked immunosorbent assay in a secondary population. In conclusion, serum proteome analysis enabled the detection/identification of existing and new candidate markers in line with fibrosis progression in HCV‐patients.

Pure laparoscopic full-left living donor hepatectomy for calculated small-for-size LDLT in adults: proof of concept.

Adult‐to‐adult living donor liver transplantation (A2ALDLT) is an accepted mode of treatment for end‐stage liver disease. Right‐lobe grafts have usually been preferred in view of the higher graft volume, which lowers the risk of a small‐for‐size syndrome. However, donor left hepatectomy is associated with less morbidity than when it is compared to right hepatectomy. Laparoscopic donor hepatectomy (LDH) has been considered almost exclusively in pediatric transplantation. The results of laparoscopic left‐liver graft procurement for calculated small‐for‐size A2ALDLT in four donors are presented. The graft‐to‐recipient body weight ratio was <0.8 in all recipients. The mean portal vein flow and the pressure and hepatic artery flows were measured at 190u2009±u200956u2009mL/min/100u2009g, 13u2009±u20091.4u2009mm/Hg and 109u2009±u200919u2009mL/min, respectively. No early postoperative donor complications were recorded. One graft was lost due to intrahepatic abscesses. Asymptomatic stenosis of a right posterior duct was treated with a Roux‐en‐Y loop 4 months later in one donor. We show that LDH of the full‐left lobe is feasible. LDH is a very demanding operation, potentially decreasing donor morbidity. Standardization of this procedure, making it accessible to the growing number of experienced laparoscopic liver surgeons, could help renewing the interest for A2ALDLT in the Western world.

Combining iodine-131 Lipiodol therapy with low-dose cisplatin as a radiosensitiser: preliminary results in hepatocellular carcinoma.

Abstract A prospective pilot trial was performed in 20 patients randomised to receive either 131I-Lipiodol therapy alone (n=10) or 131I-Lipiodol combined with a short low-dose cisplatin infusion (n=10), the aim being to evaluate the possible positive influence of a radiosensitiser on toxicity and tumour response. An activity of 1,354–2,128xa0MBq (mean 1,824xa0MBq) [36.6–57.5xa0mCi (mean 49.3xa0mCi)] 131I-labelled Lipiodol was administered by selective instillation in the hepatic artery. Cisplatin was given in a dose of 30xa0mg/m2 at day –1 and day +6 (day 0: 131I-Lipiodol). The primary endpoint of this trial was toxicity of therapy; points of secondary interest were tumour response and survival at 6 months. With the use of cisplatin we found a higher percentage of stable or diminished tumour size (90%, vs 40% without). A benefit in group survival at 6 months was not evident. Low-grade stomatitis in one patient and minor changes in peripheral blood count were probably directly related to cisplatin, but its administration is unlikely to be associated with an excess of serious side-effects. The use of low-dose cisplatin infusion as a radiosensitising agent in 131I-Lipiodol therapy for hepatocellular carcinoma seems safe and may be beneficial for tumour control. Larger patient groups are necessary for confirmation and to establish the future role of 131I-Lipiodol in hepatocellular carcinoma.

Early Arterial Revascularization After Hepatic Artery Thrombosis May Avoid Graft Loss and Improve Outcomes in Adult Liver Transplantation

BACKGROUNDnHepatic artery thrombosis (HAT) represents a devastating complication after liver transplantation (LT), occurring in 1.6%-9.2% of adult recipients. Treatments of HAT include thrombectomy and thrombolysis (with or without redo of the arterial anastomosis), percutaneous thrombolysis through an angiogram, liver retransplantation, and clinical observation.nnnMETHODSnWe retrospectively analyzed data from 739 adult LTs between January 1992 and September 2009. HAT was classified as early (E-HAT), when occurring within the first 30 days after LT, or late HAT (L-HAT), when diagnosed from the 2nd month onward. HAT suspected clinically was confirmed by Doppler ultrasound and angiography in all cases. Attempted revascularization was defined as early (ER) if performed within the first 2 weeks after LT and late (LR) if performed between 15 and 30 days.nnnRESULTSnAfter a median follow-up (FU) of 62 months (range, 1-227 months), HAT occurred in 31/739 grafts (4.3%). E-HAT was recorded in 25/31 cases (3.4%) and L-HAT in 11/31 cases (0.8%). ER was performed in 20/31 patients (65%) leading to 62% graft salvage; it was 81% when the revascularization was performed within the first week after LT (P = ns). LR was unsuccessful in all cases (P = .08). The overall incidence of BC among rescued grafts was 54% without graft loss during FU. Graft survival was 79% versus 71%; and 50% versus 50% at 1 and 3 years for E-HAT and L-HAT, respectively (P = ns).nnnCONCLUSIONSnUrgent revascularization in cases of early HAT may decrease graft loss, especially when performed within the first week after LT, with improved overall outcomes.

The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C infected patients treated with direct acting antivirals with and without Pegylated Interferon: A Belgian experience.

Recently, concerns were raised of high rates of HCC recurrence in patients treated with direct‐acting antivirals (DAA) for hepatitis C infection. We investigated the HCC occurrence and recurrence rates within 6 months after treatment with DAA with or without pegylated interferon (PEG‐IFN) in real life. This is a retrospective, multicenter cohort trial, executed in 15 hospitals distributed across Belgium. Populations were matched based on fibrosis score (Metavir F3‐F4). Patients with a Child‐Pugh score ≥ B were excluded. In total, 567 patients were included, of whom 77 were treated with PEG‐IFN+DAA between 2008 and 2013 and 490 with DAA without PEG‐IFN between 2013 and 2015. Patients treated with PEG‐IFN+DAA (53±9y) were younger than patients treated with DAA without PEG‐IFN (59±12y) (P=.001). 47% of patients treated with PEG‐IFN+DAA were in the F4 stage vs 67% of patients treated with DAA without PEG‐IFN (P=.001). Screening was inadequate in 20% of both patient groups (P=.664). The early occurrence rate of HCC was 1.7% and 1.1% in patients treated with DAA with and without PEG‐IFN, respectively (P=.540). The early recurrence rate was 0% in patients treated with PEG‐IFN+DAA and 15.0% in patients treated with DAA without PEG‐IFN (P=.857). There is no difference in early occurrence of new HCC between patients treated with DAA with and without PEG‐IFN. We did observe a high early recurrence rate of HCC in patients treated with DAA without PEG‐IFN. However, these patients were at baseline more at risk for HCC. Finally, in 20%, screening for HCC was inadequate.

Induction of tolerance in solid organ transplantation: the rationale to develop clinical protocols in liver transplantation.

Minimization or withdrawal of immunosuppressive treatments after organ transplantation represents a major objective for improving quality of life and long-term survival of grafted patients. Such a goal may be reached under some clinical conditions, particularly in liver transplantation, making these patients good candidates for tolerance trials. In this context in liver transplantation, the central questions are (1) how to promote the natural propensity of the liver graft to be accepted, (2) which type of immunosuppressive drug should be used for induction and maintenance, and (3) which biomarkers could be used to discriminate tolerant patients from those requiring long-term immunosuppression. Induction therapies using aggressive T-cell-depleting agents may favor graft acceptance. However, persistent and/or rapidly reemerging cell lines, such as memory-type cells or CD8(+) T cells, could represent a significant barrier for induction of tolerance. The type of maintenance drugs also remains questionable. Calcineurin inhibitors may be eventually deleterious in the context of tolerance protocols, through inhibitory effects on regulatory T cells, that are not observed with rapamycin. In conclusion, significant efforts must be made to achieve reliable strategies for immunosuppression minimization or withdrawal after organ transplantation into the clinics.

Improved results for adult split liver transplantation with extended right lobe grafts: could we enhance its application?

OBJECTIVEnSplit liver transplantation (SLT) allows grafting of 2 recipients with 1 allograft. Results of adult SLT have improved since its first introduction. Children benefit most from SLT, while among some adult liver transplanters there are concerns about splitting a liver, turning a good quality graft into a marginal one. We performed a single center retrospective review to address this issue.nnnPATIENTS AND METHODSnBetween June 2001 and August 2008, we performed 22 extended right liver graft (eRLG) transplantations in 21 adult patients.nnnRESULTSnEleven donors (50%) did not meet the Eurotransplant criteria for optimal donors. Forty-one percent of eRLG donors showed hemodynamic instability at the time of harvest. Eighteen (82%) splitting procedures were performed ex situ. The main indications for transplantation were alcoholic liver cirrhosis (32%), hepatitis C-related cirrhosis (18%), and acute liver failure (18%). Mean recipient age was 54 years (range, 17-69 years); median Model for End-Stage Liver Disease (MELD) score was 15 (range, 7-40). Patients were followed for a median of 16 months (range, 4-92 months) following transplantation. We observed 5 (23%) vascular and 3 (14%) biliary complications. Overall patient survival was 84% at 3 years; overall graft survival was 79%. For the 11 patients who had undergone transplantation after 2007, we observed a 100% patient and graft survival.nnnCONCLUSIONnAfter an initial learning curve and provided careful selection, exceptions to classical donor criteria for splitting can be accepted with successful outcomes comparable to those after whole liver transplantation.