Monica A. Konerman

Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 patients without cirrhosis were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%), and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56), and hepatic steatosis (aOR: 1.78) at the time of initial biopsy were marginally associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/L versus <25% values >100 U/L) were strongly associated with fibrosis progression. Conclusion: Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important noninvasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment. (Hepatology 2014;59:767–775)

Pharmacotherapy for NASH: Current and emerging

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Given the disease burden, there is an important unmet need for pharmacologic treatment options for this patient population. The underlying pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex and reflected by the myriad of therapies, with different targets, currently under investigation. In broad strokes, drug development has focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. The compounds in phase IIa have provided promising results in terms of potential benefits on various aspects of histopathology. Agents in later stages of development have shown fairly modest results in terms of reduction of hepatic steatosis, necroinflammation and fibrosis. If longer term safety and efficacy are established among heterogeneous cohorts, these medications may help mitigate potential morbidity and mortality for this burgeoning patient population.

Interferon Treatment for Hepatitis B

Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.

Systematic review: identifying patients with chronic hepatitis C in need of early treatment and intensive monitoring – predictors and predictive models of disease progression

Advances in hepatitis C therapies have led to increasing numbers of patients seeking treatment. As a result, logistical and financial concerns regarding how treatment can be provided to all patients with chronic hepatitis C (CHC) have emerged.

Improvement of predictive models of risk of disease progression in chronic hepatitis C by incorporating longitudinal data

Existing predictive models of risk of disease progression in chronic hepatitis C have limited accuracy. The aim of this study was to improve upon existing models by applying novel statistical methods that incorporate longitudinal data. Patients in the Hepatitis C Antiviral Long‐term Treatment Against Cirrhosis trial were analyzed. Outcomes of interest were (1) fibrosis progression (increase of two or more Ishak stages) and (2) liver‐related clinical outcomes (liver‐related death, hepatic decompensation, hepatocellular carcinoma, liver transplant, or increase in Child‐Turcotte‐Pugh score to ≥7). Predictors included longitudinal clinical, laboratory, and histologic data. Models were constructed using logistic regression and two machine learning methods (random forest and boosting) to predict an outcome in the next 12 months. The control arm was used as the training data set (n = 349 clinical, n = 184 fibrosis) and the interferon arm, for internal validation. The area under the receiver operating characteristic curve for longitudinal models of fibrosis progression was 0.78 (95% confidence interval [CI] 0.74‐0.83) using logistic regression, 0.79 (95% CI 0.77‐0.81) using random forest, and 0.79 (95% CI 0.77‐0.82) using boosting. The area under the receiver operating characteristic curve for longitudinal models of clinical progression was 0.79 (95% CI 0.77‐0.82) using logistic regression, 0.86 (95% CI 0.85‐0.87) using random forest, and 0.84 (95% CI 0.82‐0.86) using boosting. Longitudinal models outperformed baseline models for both outcomes (P < 0.0001). Longitudinal machine learning models had negative predictive values of 94% for both outcomes. Conclusions: Prediction models that incorporate longitudinal data can capture nonlinear disease progression in chronic hepatitis C and thus outperform baseline models. Machine learning methods can capture complex relationships between predictors and outcomes, yielding more accurate predictions; our models can help target costly therapies to patients with the most urgent need, guide the intensity of clinical monitoring required, and provide prognostic information to patients. (Hepatology 2015;61:1832–1841)

Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers

Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record–based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record–based “best practice advisory” (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti‐HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre‐BPA and post‐BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post‐BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. Conclusion: Implementation of an electronic health record–based prompt increased HCV screening rates among baby boomers in primary care by 5‐fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017;66:1805–1813)

Incidence of and Risk Assessment for Adverse Cardiovascular Outcomes After Liver Transplantation: A Systematic Review

Background Cardiovascular events represent a major source of morbidity and mortality after liver transplantation and will likely increase given the aging population and nonalcoholic fatty liver disease as a leading indication for transplant. The optimal cardiovascular risk stratification approach in this evolving patient population remains unclear. The aims of this systematic review are to: (1) refine the definition, (2) characterize the incidence, and (3) identify risk factors for cardiovascular events post-liver transplantation. Additionally, we evaluated performance characteristics of different cardiac testing modalities. Methods MEDLINE via PubMed, EMBASE, Web of Science, and Scopus were searched for studies published between 2002 and 2016 (model of end-stage liver disease era). Two authors independently reviewed articles to select eligible studies and performed data abstraction. Results Twenty-nine studies representing 57 493 patients from 26 unique cohorts were included. Definitions of cardiovascular outcomes were highly inconsistent. Incidence rates were widely variable: 1% to 41% for outcomes of 6 months or shorter and 0% to 31% for outcomes longer than 6 months. Multivariate analyses demonstrated that older age and history of cardiac disease were the most consistent predictors of cardiovascular events posttransplant (significant in 8/23 and 7/22, studies, respectively). Predictive capacity of various cardiac imaging modalities was also discrepant. Conclusions The true incidence of cardiovascular outcomes post-liver transplant remains unknown in large part due to lack of consensus regarding outcome definition. Overall, poor data quality and gaps in knowledge limit the ability to clearly identify predictors of outcomes, but existing data support a more aggressive risk stratification protocol for patients of advanced age and/or with preexisting cardiac disease.

Projected increase in obesity and non-alcoholic steatohepatitis-related liver transplantation waitlist additions in the United States

Nonalcoholic steatohepatitis (NASH) cirrhosis is the fastest growing indication for liver transplantation (LT) in the United States. We aimed to determine the temporal trend behind the rise in obesity and NASH‐related additions to the LT waitlist in the United States and make projections for future NASH burden on the LT waitlist. We used data from the Organ Procurement and Transplantation Network database from 2000 to 2014 to obtain the number of NASH‐related LT waitlist additions. The obese population in the United States from 2000 to 2014 was estimated using data from the U.S. Census Bureau and the National Health and Nutrition Examination Survey. Based on obesity trends, we established a time lag between obesity prevalence and NASH‐related waitlist additions. We used data from the U.S. Census Bureau on population projections from 2016 to 2030 to forecast obesity estimates and NASH‐related LT waitlist additions. From 2000 to 2014, the proportion of obese individuals significantly increased 44.9% and the number of NASH‐related annual waitlist additions increased from 391 to 1,605. Increase in obesity prevalence was strongly associated with LT waitlist additions 9 years later in derivation and validation cohorts (R2 = 0.9). Based on these data, annual NASH‐related waitlist additions are anticipated to increase by 55.4% (1,354‐2,104) between 2016 and 2030. There is significant regional variation in obesity rates and in the anticipated increase in NASH‐related waitlist additions (P < 0.01). Conclusion: We project a marked increase in demand for LT for NASH given population obesity trends. Continued public health efforts to curb obesity prevalence are needed to reduce the projected future burden of NASH. (Hepatology 2017).

Is It More Cost-effective for Patients With Chronic Hepatitis B to Have a Trial of Interferon Before Considering Nucleos(t)ide Analogue Therapy?

Both pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NUCs) are recommended as first line treatment options for patients with chronic hepatitis B (CHB).1 In clinical practice however, NUCs are used as first line treatment in the majority of patients due to concern about side effects and the fact that only a small proportion of patients achieve durable response with IFN therapy. IFN therapy does offer a defined treatment duration and depending on the underlying hepatitis B virus (HBV) genotype, a higher chance of hepatitis B surface antigen (HBsAg) loss and durable hepatitis B e antigen (HBeAg) loss compared to NUC therapy. 2 If a response-guided approach for IFN therapy can be implemented in a manner similar to that used in hepatitis C, PEG-IFN therapy might be more attractive because patients who are unlikely to benefit can be spared from further side effects and costs. Cost effectiveness analyses comparing different CHB treatment approaches show variable results depending on the study population, estimated rates of disease progression and treatment response, as well as costs of IFN and NUCs in each country. Thus far only one study has evaluated the cost effectiveness of IFN regimens with a 12 week response-guided stop rule. This study evaluated HBeAg-negative patients and found that first-line PEG-IFN strategies that applied either the 12 week stop rule or the full 48 week course were more cost-effective than NUCs, though the differences in quality adjusted life years (QALYs) were small.3 In this issue of the Journal, Lo et al expanded on this work by evaluating the cost-effectiveness of response-guided IFN therapy for both HBeAg-positive and HBeAg-negative patients.4 They constructed a Markov model using Hong Kong population data and rates of disease progression and treatment response from data in the literature. The primary outcome variable was the cost effectiveness ratio (CER) of different treatment strategies based on QALYs compared to no treatment using a cost effectiveness threshold of 50,000 United States Dollars (USD)/QALY. The six different treatment strategies compared included: 1) PEG-IFN with 12 week stopping rule, 2) PEG-IFN for 48 weeks, 3) entecavir monotherapy, 4) tenofovir monotherapy, 5) telbividine monotherapy, and 6) telbivudine roadmap with tenofovir switch. HBeAg seroconversion was used to define treatment response and HBsAg >20,000 IU/mL at week 12 as the stop rule for HBeAg-positive patients. For HBeAg-negative patients, response was defined as alanine aminotransferase >2 the upper limit of normal and HBV DNA >2,000 IU/mL and stop rule was no decline in HBsAg and <2 log decline in HBV DNA at week 12. The authors found that PEG-IFN therapy with a 12-week response-guided stop rule had the lowest CER (

Pre-Liver Transplant Transthoracic Echocardiogram Findings and 6-Month Post-Transplant Outcomes: A Case-Control Analysis

9501/QALY) compared to no treatment for HBeAg-positive patients, while entecavir had the lowest CER (