Dynamic prediction of risk of liver-related outcomes in chronic hepatitis C using routinely collected data.

Accuracy of risk assessments for clinical outcomes in patients with chronic liver disease has been limited given the nonlinear nature of disease progression. Longitudinal prediction models may more accurately capture this dynamic risk. The aim of this study was to construct accurate models of short- and long-term risk of disease progression in patients with chronic hepatitis C by incorporating longitudinal clinical data. Data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial were analysed (n = 533 training cohort; n = 517 validation cohort). Outcomes included a composite liver outcome (liver-related death, decompensation, hepatocellular carcinoma (HCC) or liver transplant), decompensation, HCC and overall mortality. Longitudinal models were constructed for risk of outcomes at 1, 3 and 5 years and compared with models using data at baseline only or baseline and a single follow-up time point. A total of 25.1% of patients in the training and 20.8% in the validation cohort had an outcome during a median follow-up of 6.5 years (range 0.5-9.2). The most important predictors were as follows: albumin, aspartate aminotransferase/alanine aminotransferase ratio, bilirubin, alpha-fetoprotein and platelets. Longitudinal models outperformed baseline models with higher true-positive rates and negative predictive values. The areas under the receiver-operating characteristic curve for the composite longitudinal model were 0.89 (0.80-0.96), 0.83 (0.76-0.88) and 0.81 (0.75-0.87) for 1-, 3-, and 5-year risk prediction, respectively. Model performance was retained for decompensation and overall mortality but not HCC. Longitudinal prediction models provide accurate risk assessments and identify patients in need of intensive monitoring and care.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis C virus infection.

Single nucleotide polymorphisms (SNPs) near the IL28B gene have been shown to be associated with response to treatment for chronic hepatitis C and also with spontaneous clearance of hepatitis C virus (HCV) infection. We analysed the association between IL28B genetic variants and spontaneous clearance of HCV infection in 376 HCV-infected Chinese paid plasma donors. Genotyping of eight SNPs near the IL28B region was performed by the iPLEX system (MassARRAY(®) SNP Genotyping; Sequenom) in all donors, and sequencing was performed on all 80 donors who cleared HCV and on 160 of 296 donors who did not clear HCV to validate the genotypes. Eighty (21.3%) donors spontaneously cleared HCV. Four SNPs were significantly associated with spontaneous HCV clearance: rs8099917 TT (vs GT), rs8105790 TT (vs CT), rs12980275 AA (vs AG) and rs10853728 CC (vs CG or GG) with OR (95% CI) 15.27 (2.07-112.50), 14.88 (2.02-109.72), 7.92 (1.88-33.32) and 2.32 (1.22-4.42) respectively. No association between the other four IL28B SNPs including rs12979860 and spontaneous HCV clearance was found. Women had a higher rate of spontaneous HCV clearance than men [56/213 (26.3%) vs 24/163 (14.6%), P = 0.007], and this was true even after stratification for IL28B genotypes with OR of 1.9-2.2 among those with favourable genotypes. Our results confirmed that IL28B polymorphism is associated with spontaneous clearance of HCV in Chinese subjects, but the SNPs that predict HCV clearance in Chinese subjects were different from those reported in Caucasians. Women were more likely to clear HCV infection regardless of IL28B genotypes.

Adherence to nucleos(t)ide analogues for chronic hepatitis B in clinical practice and correlation with virological breakthroughs.

Medication adherence is important for the success of nucleos(t)ide analogue (NUC) treatment for chronic hepatitis B. The aims of this study were to determine adherence to NUCs and factors associated with NUC adherence and to correlate NUC adherence with the occurrence of virological breakthroughs in patients with chronic hepatitis B. Consecutive patients with chronic hepatitis B receiving NUC were asked to complete a survey every 3 months. Adherence was also assessed by healthcare providers in the clinic. Adherence rate was defined as the per cent of days the patients took their hepatitis B virus medications during the last 30 days. A total of 111 patients were studied. The mean age was 47.7 years, 73.9% were men, 57.7% were Asian, 42.3% had postgraduate education and 80% had private insurance. Sixty-nine (74.1%) patients reported 100% adherence in the survey, while 78 (83.9%) reported 100% adherence to their healthcare providers. Patients with 100% adherence based on the survey were older (P = 0.02), more likely to be men (P = 0.006), and had higher annual household income (P = 0.04) than those with <100% adherence. In the 80 patients who completed three surveys, viral breakthrough was observed in 1/46 (2.2%) with 100% adherence on all three surveys, 1/18 (5.6%) with <100% adherence on one survey and 3/16 (18.8%) with <100% adherence on ≥2 surveys, (P = 0.06). In conclusion, adherence to NUC therapy in our patients with chronic hepatitis B was high but self-reporting of adherence to healthcare providers may be inflated. Patients with chronic hepatitis B with better adherence to NUC therapy had a trend towards a lower rate of viral breakthroughs.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Variation in organ quality between liver transplant centers.

A wide spectrum of quality exists among deceased donor organs available for liver transplantation. It is unknown whether some transplant centers systematically use more low quality organs, and what factors might influence these decisions. We used hierarchical regression to measure variation in donor risk index (DRI) in the United States by region, organ procurement organization (OPO) and transplant center. The sample included all adults who underwent deceased donor liver transplantation between January 12, 2005 and February 1, 2009 (n = 23,810). Despite adjusting for the geographic region and OPO, transplant centers' mean DRI ranged from 1.27 to 1.74, and could not be explained by differences in patient populations such as disease severity. Larger volume centers and those having competing centers within their OPO were more likely to use higher risk organs, particularly among recipients with lower model for end-stage liver disease (MELD) scores. Centers using higher risk organs had equivalent waiting list mortality rates, but tended to have higher post-transplant mortality (hazard ratio 1.10 per 0.1 increase in mean DRI). In conclusion, the quality of deceased donor organ patients receive is variable and depends in part on the characteristics of the transplant center they visit.

Characteristics of chronic hepatitis B patients who underwent liver biopsies.

Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10-year period were reviewed. Significant liver disease was defined as Knodell HAI ≥ 7 and/or Ishak fibrosis ≥ 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety-three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log(10) copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.

Endpoints of hepatitis B treatment.

The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies.

Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation.

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.

Hepatitis B: liver fibrosis and hepatocellular carcinoma.

Chronic hepatitis B virus (HBV) infection is estimated to be the cause of 55-60% of hepatocellular carcinoma (HCC) in the world. It has been estimated that up to 40% of HBV-related HCC occur in persons who do not have cirrhosis while almost all cases of hepatitis C virus (HCV)-related HCC occur in the setting of cirrhosis. Data on the performance of non-invasive tests for liver fibrosis in patients with hepatitis B are limited. FibroTest may be superior to the Forns index, APRI, Goteborg University Cirrhosis Index (GUCI) and Hui model in detecting significant fibrosis (Metavir>F2) or cirrhosis (Metavir F4) but an algorithm that uses APRI for screening, FibroTest for confirmation, and biopsy for indeterminate cases has the greatest accuracy. Liver stiffness correlates with fibrosis stages but may be influenced by necroinflammatory activity with falsely high values in patients with alanine aminotransferase (ALT) flares and falsely low values in patients with viral suppression and ALT normalization during antiviral therapy. Therefore, additional studies are needed to determine the clinical settings in which liver stiffness measurement can accurately predict liver fibrosis and to establish cutoff values for differentiating different stages of fibrosis or cirrhosis. These studies should also compare the performance of liver stiffness measurement with serum markers of fibrosis in patients with varying degrees of necroinflammation and in untreated patients as well as patients receiving antiviral therapy. Until recently, older age, male gender and cirrhosis were the major risk factors associated with HCC development. Recent studies showed that HBV replication status, HBV genotype and mutations in the basal core promoter region play an important role in HCC development. These data indicate that algorithms incorporating demographics, viral factors, degree of necroinflammation and extent of fibrosis may be more accurate in predicting the risk of HBV-related HCC than fibrosis staging alone.

Recipient morbidity after living and deceased donor liver transplantation: findings from the A2ALL Retrospective Cohort Study.

Patients considering living donor liver transplantation (LDLT) need to know the risk and severity of complications compared to deceased donor liver transplantation (DDLT). One aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) was to examine recipient complications following these procedures. Medical records of DDLT or LDLT recipients who had a living donor evaluated at the nine A2ALL centers between 1998 and 2003 were reviewed. Among 384 LDLT and 216 DDLT, at least one complication occurred after 82.8% of LDLT and 78.2% of DDLT (p = 0.17). There was a median of two complications after DDLT and three after LDLT. Complications that occurred at a higher rate (p < 0.05) after LDLT included biliary leak (31.8% vs. 10.2%), unplanned reexploration (26.2% vs. 17.1%), hepatic artery thrombosis (6.5% vs. 2.3%) and portal vein thrombosis (2.9% vs. 0.0%). There were more complications leading to retransplantation or death (Clavien grade 4) after LDLT versus DDLT (15.9% vs. 9.3%, p = 0.023). Many complications occurred more commonly during early center experience; the odds of grade 4 complications were more than two-fold higher when centers had performed 40). In summary, complication rates were higher after LDLT versus DDLT, but declined with center experience to levels comparable to DDLT.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End-Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States.

The role of hepatitis B virus (HBV) genotypes in the outcome of acute HBV infection is unclear. In this study, we aimed to evaluate the clinical and virological features of patients with hepatitis B-related acute liver failure (HBV-ALF) in the US. Clinical and laboratory features of consecutive patients with HBV-ALF from the US ALF Study Group were analysed. Prevalence of HBV genotypes, precore stop (G1896A) and core promoter dual (T1762A, A1764T) variants among patients with HBV-ALF were compared with a cohort of 530 patients with chronic HBV infection. Thirty-four HBV-ALF patients were studied: mean age 41 years, 56% men, 25 had detectable HBV-DNA. HBV genotypes A, B, C and D were found in 36, 24, 8 and 32% patients, respectively. Precore stop and core promoter dual variants were detected in 32 and 44% of patients, respectively. Twenty-three (68%) patients survived: 14 after liver transplant, nine without transplant. Older age was the only independent factor associated with poor outcome. Compared with patients with chronic HBV infection, patients with ALF were more likely to be non-Asians (88% vs 44%, P = 0.005) and to have genotype D (32% vs 10%, P < 0.01). A higher prevalence of HBV genotype D persisted even after matching for race and HBeAg status (32% vs 16%, P = 0.007). We concluded that HBV genotype D was more frequently found in patients with HBV-ALF than those with chronic HBV infection in the US. Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection.

Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B.

Lamivudine has demonstrated efficacy for the treatment of hepatitis B e antigen-negative chronic hepatitis B (e-CHB). However, treatment withdrawal after 1 year has been associated with a high rate of relapse while long-term treatment is associated with increasing risks of drug resistance. We report our treatment experience of 50 Chinese-Canadian patients with e-CHB. All patients received lamivudine for 2 years. Treatment was withdrawn at month 24 in patients who had undetectable hepatitis B virus (HBV) DNA by PCR and normal aminotransferases during the second year of therapy. All patients had HBV genotype B or C. Biochemical response at months 6, 12 and 24 was 74%, 71% and 66%, respectively. HBV DNA was undetectable at months 6, 12 and 24 by hybrid capture and PCR assays in 100%, 92% and 86%; and 94%, 88% and 74% patients, respectively. The cumulative rates of genotypic resistance (GR) after 1 and 2 years were 15% and 25%, respectively. Four (44%) patients with GR experienced a hepatitis flare. The probability of clinical and virological relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively. Reinstitution of lamivudine resulted in prompt virological and biochemical responses. Our study demonstrates that a sustained response can be achieved after a 2-year course of lamivudine in a subset of patients with e-CHB.

World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants.

Hepatitis B is a serious disease that is endemic in many parts of the world. A significant proportion of patients with chronic hepatitis B (CHB) are infected with a variant form of the hepatitis B virus (HBV) which decreases or abolishes the production of hepatitis B e-antigen (HBeAg). The purpose of this literature review is to describe the epidemiology of HBeAg-negative CHB (e-CHB) worldwide. A literature search was conducted to identify studies pertaining to e-CHB and underlying variants (precore and core promoter). Fifty studies were included in our analysis. The median prevalence of e-CHB among patients with chronic HBV infection was 33% in the Mediterranean, 15% in Asia Pacific, and 14% in the USA and Northern Europe. The pre core stop codon variant was detected in a median of 60% (range 0-100%) of HBeAg-negative patients overall, 92% in the Mediterranean, 50% in Asia Pacific and 24% in the USA and Northern Europe. There were very few data on the prevalence of core promoter variants outside Asia where the median prevalence among HBeAg-negative patients was 77%. This literature review revealed that e-CHB is more common than previously suspected and that it is present worldwide with marked variations in the prevalence of associated HBV variants across different geographical regions. Additional research using population based samples of adequate size based on a consensus definition of e-CHB and using standardized HBV DNA assays is needed to better estimate the true prevalence of e-CHB and its associated HBV variants.