Low incidence of hepatitis B e antigen seroconversion in patients treated with oral nucleos(t)ides in routine practice.

BACKGROUND AND AIM: Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates. METHODS: We conducted a retrospective cohort study of 333 consecutive treatment-naïve HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion-loss of HBeAg and antibody to HBeAg (anti-HBe) development. RESULTS: The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26-52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA < 7.5 log10 IU/mL (hazard ratio [HR] = 2.59 [1.04-6.44]), P = 0.041) and alanine transaminase (ALT) > 1.5 × upper normal limit (HR = 2.86 [1.05-7.81], P = 0.040), but not the choice of nucleos(t)ides. CONCLUSIONS: The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points.

High frequency of recurrent viremia after hepatitis B e antigen seroconversion and consolidation therapy.

BACKGROUND: The primary treatment endpoint for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is HBeAg seroconversion; however, data on the durability of response are inconsistent. GOALS: Our goal was to investigate the rate of recurrent viremia after HBeAg seroconversion and subsequent discontinuation of therapy. METHODS: We retrospectively studied 88 consecutive Asian American patients who achieved HBeAg seroconversion [loss of HBeAg and development of antibody to HBeAg (anti-HBe)] among 458 HBeAg-positive patients who received oral antiviral therapy at 3 US clinics between March 1998 and November 2010. Recurrent viremia was defined as reappearance of detectable serum hepatitis B virus DNA (>100 IU/mL) on 2 consecutive laboratory tests from previously undetectable levels. RESULTS: Antiviral medications used at the time of HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), and combination therapy (3%). Antiviral therapy was continued after HBeAg seroconversion in 49 patients (group I) and discontinued in the other 39 patients after consolidation therapy [median=12 months (range, 1 to 55 mo)] (group II). No patients in group I experienced recurrent viremia, whereas 90% in group II did. Elevated alanine aminotransferase also occurred in 38% of group II patients [median peak alanine aminotransferase 249 IU/mL (range, 93 to 1070 IU/mL)]. CONCLUSIONS: Despite consolidation therapy, almost all patients who discontinued therapy after achieving HBeAg seroconversion and complete viral suppression experienced recurrent viremia, and close to half also experienced biochemical flares. HBeAg seroconversion does not seem to be a durable treatment endpoint for many patients, and they should be monitored carefully for virologic relapse and biochemical flares if antiviral therapy is withdrawn.

Risk factors for hepatocellular carcinoma in patients with chronic liver disease: a case-control study.

The majority of data on risk factors (RFs) for hepatocellular carcinoma (HCC) comes from studies involving populations without underlying liver disease. It is important to evaluate RFs for HCC in patients with chronic liver disease since HCC rarely occurs in those without underlying liver disease. We conducted a hospital-based case-control study of 259 incident HCC cases and 781 controls by convenience sampling between 02/2001 and 12/2009 from the liver clinic at Stanford University Medical Center. The study population was 41% White, 14% Hispanic, 3% African American, 40% Asian American, and 2% other race/ethnicity. RFs were examined through medical records and an in-person questionnaire. Alcohol and tobacco use was calculated by cumulative grams of alcohol or cumulative pack(s) of cigarette consumed over one's lifetime. Diabetes mellitus (DM) was defined by random glucose level of ≥200 mg/dL. RFs were evaluated using multivariate logistic regression. Independent predictors of HCC risk, after mutual adjustment and additional control for alcohol use, etiology of liver diseases, and DM, included age >40 (OR = 8.5 [2.6-28.3]), male gender (OR = 3.5 [2.2-5.8]), presence of cirrhosis (OR = 2.8 [1.6-4.9]), Asian ethnicity (OR = 2.8 [1.8-4.6]), AFP > 50 (OR = 4.2 [2.6-6.8]), and cumulative lifetime tobacco use of >11,000 packs (OR = 1.7 [1.0-2.9]). Heavy prolonged cigarette smoking, but not alcohol use, was a significant independent predictor for HCC in patients with underlying liver disease. Besides older age, male gender, presence of cirrhosis, and elevated AFP, Asian ethnicity and heavy cumulative tobacco use are strong independent predictors of HCC.

High rate of unemployment after liver transplantation: analysis of the United Network for Organ Sharing database.

The goal of liver transplantation (LT) is to maximize the length and quality of a patient's life and facilitate his or her return to full productivity. The aims of this study were (1) to use the United Network for Organ Sharing (UNOS) data set to determine the proportions of recipients who were employed and unemployed within 24 months after LT between 2002 and 2008 and (2) to examine the factors associated with a return to employment. UNOS data that were collected since the adoption of the Model for End-Stage Liver Disease scoring system on February 27, 2002 were analyzed. There were 21,942 transplant recipients who met the inclusion criteria. The employment status of the recipients was analyzed within a 60-day window at the following times after transplantation: 6, 12, and 24 months. Approximately one-quarter of the LT recipients (5360 or 24.4%) were employed within 24 months after transplantation, and the remaining recipients had not returned to work. The demographic variables that were independently associated with posttransplant employment included an age of 18 to 40 years, male sex, a college degree, Caucasian race, and pretransplant employment. Patients with alcoholic liver disease had a significantly lower rate of employment than patients with other etiologies of liver disease. The recipients who were employed after transplantation had significantly better functional status than those who were not employed. In conclusion, the employment rate after LT is low, with only one-quarter of LT recipients employed. New national and individual transplant program policies are needed to assess the root causes of unemployment in recipients who wish to work after LT.

Hepatitis B: modern end points of treatment and the specter of viral resistance.

The goal of antiviral treatment of chronic hepatitis B is to prevent the complications of cirrhosis, hepatic decompensation, HCC, and death. Because these clinical outcomes may take a long period of time to develop, it is important to use intermediate or surrogate end points to evaluate the efficacy and response to antiviral treatment, and to determine whether treatment can be safely stopped, especially given concern for the development of antiviral resistance with NUC therapy. Although normalization of ALT and suppression of HBV DNA viral replication are associated with favorable outcomes, the durability of their response is low, and these end points are insufficient markers for stopping treatment. HBeAg seroconversion is currently used to discontinue NUC treatment in patients with HBeAg-positive chronic hepatitis B, whereas the stopping rule for HBeAg-negative disease relies on HBsAg loss. However, HBsAg loss occurs very infrequently and is not a practical end point for clinical use, although quantitative HBsAg levels may be useful in identifying patients who could achieve a sustained virologic response to treatment.

IL-28B As a Predictor of Sustained Virologic Response in Patients with Chronic Hepatitis C Virus Infection.

Genome-wide association studies have recently identified single nucleotide polymorphisms in proximity to the interleukin-28B (IL-28B) gene that can predict sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection who are undergoing therapy with pegylated interferon (IFN) a and ribavirin. IL-28B encodes IFN-λ3, a type III IFN involved in host antiviral immunity. Favorable variants of the 2 most widely studied IL-28B polymorphisms, rs1 2979860 and rs8099917, are strong pretreatment predictors of early viral clearance and SVR in patients with genotype 1 HCV infection. Variations in the distribution of IL-28B alleles may partly explain differences in SVR rates among ethnic groups. Further investigations have implicated IL-28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL-28B may be a key factor involved in host immunity against HCV. Clinical trials of IFN-λ as a therapeutic agent for chronic HCV infection are currently underway. The use of IL-28B polymorphisms as a predictive tool will have a major impact on treatment strategies for chronic HCV infection, particularly in the context of emerging therapies and direct-acting antiviral agents.

High rate of complete viral suppression with combination therapy in patients with chronic hepatitis B and prior treatment failure.

BACKGROUND: Combination therapy for chronic hepatitis B virus (HBV) infection is recommended for patients with antiviral resistance (AVR) or partial response (PR) to earlier antiviral therapy; however, data on outcomes are limited. GOALS: To determine the rate of complete viral suppression (CVS) with combination therapy and to compare CVS among different indications and treatment regimens. METHODS: A cohort of 109 consecutive patients with chronic hepatitis B from 3 liver clinics in Northern California was retrospectively studied. All patients started combination therapy between April 2004 and August 2009 for the following indications: AVR (n = 29), PR (n = 60), or others (n = 20). Combination treatments included lamivudine (LAM), adefovir (ADV), telbivudine (LdT), entecavir (ETV), tenofovir (TDF), and emtricitabine (FTC). CVS was defined as undetectable serum HBV DNA <100 IU/mL. RESULTS: Among the patients, who were nearly all Asian (99%), 73% had ≥ 2 prior treatments and 82% had treatment failure (AVR or PR). Median treatment duration of combination therapy was 21 months (range, 6 to 50 mo). The majority (77%) achieved CVS after 6 months of various combination regimens: 80% for ETV+TDF, 76% for TDF+LAM or FTC or LdT, 75% for ETV+ADV, and 69% for ADV+LAM or LdT (P = 0.86). After 6 months of therapy, CVS was observed in a similar proportion of patients treated for PR and AVR (72% and 74%, respectively). CONCLUSIONS: Although the majority of 109 treatment-experienced patients had prior treatment failure, high rates of CVS were rapidly achieved and did not significantly differ between indications of AVR and PR or between ETV-based and TDF-based regimens.

Diagnosis of hepatocellular carcinoma: role of tumor markers and liver biopsy.

Early diagnosis of hepatocellular carcinoma (HCC) has a significant impact on survival by implementation of effective treatment strategies, including hepatic resection, locoregional ablative therapy, and liver transplantation. The use of serum tumor markers and biopsy are particularly important for diagnosis of small hepatic lesions with atypical features on imaging studies. α-Fetoprotein remains the most frequently used tumor marker for the diagnosis of HCC. The development of novel serum biomarkers for HCC, identification of molecular markers for tissue immunohistochemistry, and emergence of new diagnostic techniques such as proteomic profiling may improve the early detection rate of HCC in the future.

Ethnic differences in viral dominance patterns in patients with hepatitis B virus and hepatitis C virus dual infection.

UNLABELLED: Studies of hepatitis B virus (HBV)/hepatitis C virus (HCV) dual infection are limited. Most are small, conducted outside the United States, and compare dual infection with HCV monoinfection. The goal of this study was to characterize HBV/HCV dual infection in a large multiethnic, matched, case-control study of dual-infected and HBV-monoinfected patients at two United States centers. Using an International Classification of Disease Version 9 electronic query and chart review, we identified 115 HBV/HCV dual-infected patients with serial HBV DNA, HCV RNA, and alanine aminotransferase (ALT) levels. As a control, 115 HBV-monoinfected patients were chosen randomly and matched with cases by age ±10 years, sex, Asian versus non-Asian ethnicity, and study site. Both groups had similar sex, ethnic, and age distributions (68% male, 83% Asian, age 52 ± 14 years). The median follow-up times were 33 and 38 months for the dual-infected and monoinfected groups, respectively. More monoinfected patients received HBV antiviral therapy than dual-infected patients (43% versus 24%; P = 0.002). No significant difference was detected between the proportion of monoinfected versus dual-infected patients with ALT above 40 U/L at presentation or during follow-up. Dual infection patients exhibited very little HBV/HCV codominance at baseline and throughout follow-up: patients had either HBV viremia with low or absent HCV RNA or detectable HCV RNA with low or absent HBV DNA. Asian ethnicity was predictive of HBV dominance after adjusting for sex, age, and baseline ALT elevation (odds ratio 7.35; P = 0.01). CONCLUSION: HBV/HCV dual-infected and HBV-monoinfected patients had similar clinical characteristics. Asian ethnicity is a major independent predictor of HBV-dominant disease, and HCV dominance with undetectable HBV DNA is more common in non-Asian individuals. Larger studies are needed to further characterize the natural history of HBV/HCV dual infection in Asian and non-Asian individuals.

Chronic viral hepatitis: epidemiology, molecular biology, and antiviral therapy.

Viral hepatitis is a major cause of chronic liver disease, liver failure, and hepatocellular carcinoma worldwide, resulting in significant morbidity and mortality. New insights into the pathogenesis and molecular biology of hepatitis viruses have led to the discovery of novel antiviral agents. Likewise, a greater understanding of the natural history of chronic infection, predictors of disease progression, and predictors of virologic response to therapy has resulted in more effective treatment strategies. Recent data have increasingly demonstrated that the ability to achieve a successful response to antiviral therapy may significantly reduce the risk of progressive liver disease and hepatocellular carcinoma. Immunization practices and the use of potent antiviral therapy may have a major impact in reducing the burden of chronic liver disease and the incidence of hepatocellular carcinoma associated with chronic hepatitis B and chronic hepatitis D. Individualized treatment strategies and the development of direct acting antiviral agents may lead to further improvements in the ability to achieve a sustained virologic response to therapy in chronic hepatitis C. With new advances in the treatment of chronic hepatitis, efforts to optimize viral suppression while reducing the potential for antiviral drug resistance will become increasingly important.

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study.

BACKGROUND: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV-related HCC is increasing, while the number of patients listed for HBV-related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. RESULTS: Ninety-eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV-related HCC. With a mean follow-up of 36.5 months post-OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre-OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre-OLT in predicting HCC recurrence. Serum alpha-fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p=0.003). HCC recurrence was significantly associated with decreased post-OLT survival. CONCLUSION: HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence.

Long-term effects of antiviral therapy in patients with chronic hepatitis C.

Chronic hepatitis C is a major cause of chronic liver disease globally, and the natural history of progression may lead to cirrhosis with liver failure, hepatocellular carcinoma, and premature liver-related death. Emerging data demonstrates that interferon-based therapy, particularly among those achieving a sustained virologic response (SVR), is associated with long-term persistence of SVR, improved fibrosis and inflammation scores, reduced incidence of hepatocellular carcinoma, and prolonged life expectancy. This reduction in the rate of progression has also been demonstrated in patients with chronic hepatitis C and cirrhosis in some but not all studies. The majority of these results are reported with standard interferon therapy, and long-term results of peginterferon plus ribavirin therapy with a higher likelihood of SVR should have a yet greater impact on the population of treated patients. The impact on slowing progression is greatest in patients with an SVR, less in relapsers, and equivocal in nonresponders. Thus, the natural history of chronic hepatitis C after completion of antiviral therapy is favorable with achievement of an SVR, although further data are needed to determine the likely incremental impact of peginterferon plus ribavirin, late long-term effects of therapy, and the benefit of treatment in patients with advanced hepatic fibrosis.

Diabetes mellitus increases the risk of mortality following liver transplantation independent of MELD score.

BACKGROUND: Patients with diabetes mellitus overall experience worse health outcomes than non-diabetics, but whether this is true among recipients of liver transplantation still remains unclear. The aim of this study was to compare the mortality of diabetic and non-diabetic patients following liver transplantation. METHODS: We conducted a retrospective analysis of 530 adult patients undergoing liver transplantation at Stanford University Medical Center from February 1995 to July 2006. Information on diabetes mellitus was available for 431 patients; 96 patients who had acute liver failure (n = 17), combined liver and kidney transplantation (n = 28), or died prior to discharge (n = 51) were excluded from analysis. RESULTS: Over a mean follow-up of 4.5 years, survival was 81% in the diabetic group and 94% among controls (p = <0.0001). After controlling for age (mean +/- SD: 54.4 +/- 7.6 in diabetics, 50.1 +/- 9.6 in controls), body mass index (28.6 +/- 6.6 in diabetics, 27.1 +/- 5.4 in controls), presence of hepatitis C, and MELD score (17 +/- 9.6 in diabetics, 19 +/- 10.2 in controls), diabetes mellitus remained a significant predictor of death (HR 3.11, p = 0.01). CONCLUSIONS: Diabetes mellitus is an independent risk factor for mortality following liver transplantation. Further investigation of this relationship should focus on the impact of more intensive pre- and post-liver transplantation glucose control, cardiovascular risk factor reduction, and the effects of accelerated atherosclerosis in the setting of immune suppression.

An explicit quality indicator set for measurement of quality of care in patients with cirrhosis.

BACKGROUND & AIMS: Cirrhosis is a prevalent and expensive condition. With an increasing emphasis on quality in health care and recognition of inconsistencies in the management of patients with cirrhosis, we established a set of explicit quality indicators (QIs) for their treatment. METHODS: We organized an 11-member, multidisciplinary expert panel and followed modified Delphi methods to systematically identify a set of QIs for cirrhosis. We provided the panel with a report that summarized the results of a comprehensive literature review of data linking candidate QIs to outcomes. The panel performed independent ratings of each candidate QI by using a standard 9-point RAND appropriateness scale (RAS) (ranging from 1 = not appropriate to 9 = most appropriate). The panel members then met, reviewed the ratings, and voted again by using an iterative process of discussion. The final set of QIs was selected; QIs had a median RAS >7, and panel members agreed on those selected. RESULTS: Among 169 candidate QIs, the panel rated 41 QIs as valid measures of quality care. The selected QIs cover 6 domains of care including ascites (13 QIs), variceal bleeding (18 QIs), hepatic encephalopathy (4 QIs), hepatocellular cancer (1 QI), liver transplantation (2 QIs), and general cirrhosis care (3 QIs). Content coverage included prevention, diagnosis, treatment, timeliness, and follow-up. CONCLUSIONS: We developed an explicit set of evidence-based QIs for treatment of cirrhosis. These provide physicians and institutions with a tool to identify processes amenable to quality improvement. This tool is intended to be applicable in any setting where care for patients with cirrhosis is provided.

Liver biopsy for histological assessment: The case against.

Percutaneous liver biopsy (LB) remains an important tool in the diagnosis and management of parenchymal liver diseases. In current practice, it is most frequently performed to assess the inflammatory grade and fibrotic stage of commonly encountered liver diseases, with the diagnostic role relegated to secondary importance. The role of LB remains a vastly controversial and debated subject, with an ever-increasing burden of evidence that questions its routine application in all patients with liver dysfunction. It remains, essentially, an invasive procedure with certain unavoidable risks and complications. It also suffers shortcomings in diagnostic accuracy since a large liver sample is required for an ideal assessment, which in clinical practice is not feasible. LB is also open to observer interpretation and prone to sampling errors. In recent years, a number of noninvasive biomarkers have evolved, each with an impressive range of diagnostic certainty approaching that achieved with LB. These noninvasive tests represent a lower-cost option, are easily reproducible, and serve as suitable alternatives to assess hepatic inflammation and fibrosis. This article aims to debate the shortcomings of LB while simultaneously demonstrating the diagnostic accuracy, reliability and usefulness of noninvasive markers of liver disease thereby making the case for their utilization as suitable alternatives to LB in many, although not all, circumstances.

Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide.

GOALS: The primary aim of this study was to further evaluate the efficacy of peginterferon plus nitazoxanide without ribavirin using a 4-week lead-in. BACKGROUND: The initial treatment of chronic hepatitis C with nitazoxanide used 12 weeks of nitazoxanide monotherapy before combination therapy with peginterferon with or without ribavirin. STUDY: This open-label pilot study enrolled 44 treatment-naive patients with chronic hepatitis C (40 with genotype 4; 3 with genotype 1; and 1 with genotype 2). The patients received oral nitazoxanide 500 mg twice daily for 4 weeks followed by nitazoxanide plus peginterferon alfa-2a 180 mug weekly for 36 weeks and were then followed for 24 weeks. The results of this study were compared with those from an overlapping historical trial using 12 weeks of nitazoxanide lead-in. RESULTS: A sustained virologic response (SVR) was achieved in 80% of patients, which was similar to the SVR rates in the historical trial, that is, 79% and 61% in patients treated with and without ribavirin, respectively. A rapid virologic response occurred in 59% of patients, which was also similar to the rapid virologic response rates in the historical trial (64% and 54% in patients treated with and without ribavirin, respectively). All 4 patients with genotypes 1 and 2 had an SVR. CONCLUSIONS: The nitazoxanide lead-in phase before combination therapy with peginterferon can likely be reduced from 12 weeks to 4 weeks without compromising virologic response rates. In addition, treatment of chronic hepatitis C with peginterferon plus nitazoxanide without ribavirin is promising and requires further study.