I. Carey

Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease

Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created, but remain independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting with fulminant liver failure who required liver transplant. Patients with AIH and non‐AIH etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity, and positive and negative predictive values for scores of ≥6 (probable AIH) and ≥7 (definite AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221 with AIH, 26 with variant syndromes, and 302 with non‐AIH). For scores ≥6, sensitivity was 90%, and specificity was 98% with positive and negative predictive values of 97% and 92%, respectively. For scores ≥7; sensitivity was 70%, and specificity was 100% with positive and negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified criteria and 40% for 1999 criteria, respectively. Conclusion: The simplified criteria retain high specificity but exhibit lower sensitivity for scores of ≥7. The explanations for this are unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations. (HEPATOLOGY 2009.)

Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians

Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82–212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. Conclusions Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.

Prospective comparison of Fibroscan, King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection

Summary.  Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King’s score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty‐seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono‐infection (HCV RNA‐positive by RT‐PCR), attending King’s College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3–F6, and cirrhosis defined as Ishak fibrosis F5–F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43–54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3–F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (≥F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut‐off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3–F6.

Immune and Viral Profile from Tolerance to Hepatitis B Surface Antigen Clearance: a Longitudinal Study of Vertically Hepatitis B Virus-Infected Children on Combined Therapy

ABSTRACT The aim of the study was to investigate longitudinally hepatitis B virus (HBV)-specific T-cell reactivity and viral behavior versus treatment response in tolerant children during combined antiviral therapy. Twenty-three children with infancy-acquired hepatitis B (HBeAg+) belonging to a published pilot study of 1-year treatment with lamivudine/alpha interferon (IFN-α) were investigated. Five seroconverted to anti-HBs (responders). Nine were HLA-A2+ (4 responders and 5 nonresponders). Mutations within the HBV core gene were determined at baseline in liver and in serial serum samples by direct sequencing at baseline; during treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24) and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16 HBV core 20-mer overlapping peptides and by HLA-A2-restricted core18-27 pentamer staining and CD8+ IFN-γ enzyme-linked immunospot (ELISPOT) assay. HBV core-specific T-cell proliferative and CD8 responses were more vigorous and broader among responders than among nonresponders at TW28 and TW52, while the number of mutations within HBV core gene immunodominant epitopes was lower at TW28 and was negatively associated with HBV-specific T-cell proliferative responses at both time points. The HBV DNA viral load was negatively associated with HBV-specific T-cell proliferative and CD8 responses during treatment, especially at TW28. Treatment-induced transition from immunotolerance to HBV immune control is characterized by the emergence of efficient virus-specific immune responses capable of restraining mutations and preventing viral evasion.

Monotherapy versus combination therapy for the treatment of chronic hepatitis B

Background: Nucleos(t)ide analogues, active against hepatitis B polymerase, suppress viral replication and improve clinical outcome. However, the emergence of drug-resistant mutants can result in treatment failure. Objectives: We describe how the choice of first-line therapy is critical to long-term treatment success. Methods: A review of current drug therapies is provided. Results/conclusions: Monotherapy with early-generation drugs (lamivudine or adefovir) was associated with a high rate of viral drug resistance and combination therapy with these agents was shown to reduce the incidence of resistance. The latest-generation drugs (entecavir and tenofovir) are potent inhibitors of viral replication and, in treatment-naive subjects, viral resistance to entecavir is uncommon and is not yet reported to tenofovir. Therefore, monotherapy with either entecavir or tenofovir is the current preferred option in treatment-naive patients. Combination therapy is appropriate in those with drug-resistant HBV infection, where drug choice is guided by the viral drug-resistance genotype/phenotype. Although combination therapy has been advocated in other patient groups (e.g., those with decompensated cirrhosis and following liver transplantation), there are, as yet, no data to mandate the use of combination therapy in such patients and any perceived benefit must be weighed against increased cost and risk for toxicity.

Recurrent HCV after liver transplantation—mechanisms, assessment and therapy

Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed.

Tenofovir-based combination therapy for HIV/HBV co-infection: factors associated with a partial HBV virological response in patients with undetectable HIV viraemia.

Objective:The aim of this study was to identify and describe patients with detectable hepatitis B virus (HBV) DNA in the presence of undetectable HIV RNA after 48 weeks of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) treatment. Design:Case–control study. Cases or delayed responders were defined as detectable HBV DNA (>20 IU/ml) with undetectable HIV RNA (<40 c/ml) after 48 weeks TDF/3(F)TC combination therapy. Controls or virological responders were defined as both undetectable HIV and HBV after 48 weeks TDF/3(F)TC therapy. Results:Twenty-three cases were identified and matched to 24 controls. 87% cases and 46% controls were eAg-positive (P = 0.005). Nine of 23 (39%) cases and seven of 24 (29%) controls had 3TC monotherapy prior to TDF. Similar proportions had 3TC/FTC resistance pre-TDF (30% cases, 24% controls). The cases had significantly higher baseline HBV DNA pre-3TC (median 1.2 × 108 vs. 3.1 × 106IU/ml; P = 0.009) and pre-TDF (1.1 × 108 vs. 2.6 × 104 IU/ml; P = 0.012). Sixteen of 23 cases eventually achieved undetectable HBV DNA after 42.2 (27.2, 54.9) months. Six of 23 still have detectable HBV DNA after 46.2 (28.2, 65.6) months. Only one delayed responder patient developed a new 3(F)TC mutation and they received intensification with entecavir and achieved undetectable HBV DNA. No patient developed TDF resistance. Conclusion:We report the largest series of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This outcome was associated with positive eAg and higher baseline HBV DNA. Our data suggest that clinicians should not intensify therapy with entecavir unless there is evidence of new 3TC/FTC mutations as the majority of patients go on to suppress HBV. TDF resistance was not seen.

Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients.

Recently, the therapeutic landscape with regard to anti‐HCV therapy has changed dramatically. The new directly acting anti‐virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated‐interferon and ribavirin.

Hepatitis E--an unexpected problem at home.

While viral hepatitis in Europe has mainly focused on hepatitis B and C, there is emerging evidence to suggest that hepatitis E is an overlooked sporadic infection in industrialized countries. In the UK, France and Japan for instance, it is more common than hepatitis A infection, occurring in patients without foreign travel. The incidence of autochthonous hepatitis E virus (HEV) infection is uncertain. Moreover, HEV in developed countries affect the middleaged to elderly and is associated with higher mortality than endemic infection. HepatitisEcanmanifestwithextrahepatic symptoms. We report a 56-year-old Caucasian who presented with acute upper limb pain andweakness. Incidental finding of elevated transaminase (AST 234 IU/l, bilirubin 30 mmol/l) led to the discovery of HEV IgM antibodies and positive HEV viral titer. There was no obvious risk factor for acquiring infectionapart fromconsumptionof porksausage,swinereservoir isthoughttoberesponsible for locally acquired cases in developed countries. Within 1 week the liver enzyme derangement normalized and serum clearance of virus occurred by 6 weeks. However, the patient experienced ongoing limb pain 10 months following HEV infection. The neurological deficit was consistent with brachial neuritis, one of the commonest forms of neuropathy associated with HEV. There are fewer than 20 reports of neurological manifestations of hepatitis E, including those of chronic liver disease in immunocompromised patients. Treatment with immunoglobulin or plasmaphoresis did not produce consistent result in this small population. Thus, it is important to consider hepatitis E when investigating patients with liver injury, who may otherwise be diagnosed as drug-related or seronegative hepatitis. It is also obsolete to think of HEV only as an infection causing acute hepatitis in developing countries [1].

Development and validation of an efficient in-house real-time reverse transcription polymerase chain reaction assay for the quantitative detection of serum hepatitis delta virus RNA in a diverse South London population.

Hepatitis delta virus (HDV) causes both acute and chronic hepatitis, always in the presence of hepatitis B. Analysis of global HDV isolates has shown that at least eight genotypes exist. HDV RNA quantitation and genotyping are important tools in the diagnosis and management of infected individuals. There is, as yet, no commercially available quantitative HDV RNA assay. Several laboratories have developed in-house assays, but equivalent detection and quantitation across all HDV genotypes has not been demonstrated. In this study, the development of an in-house real-time reverse transcription polymerase chain reaction (RT PCR) assay is described to quantify HDV RNA in serum or plasma. Its efficiency was validated by testing 99 samples from patients with known chronic HDV infection, along with 22 samples from individuals without HDV. The assay has a dynamic range of 6.4×10(2) to 6.4×10(8)copies/mL. Amplicons of the quantitative PCR can be directly used for sequence analysis and genotyping. HDV-1, HDV-5 and HDV-6 were identified, reflecting the areas of origin of our cohort of patients. The ability to genotype and to accurately quantify HDV RNA levels in the more recently discovered African genotypes will be important for investigating the natural history of HDV in this group, compared to those with genotype 1 disease.