Hepatic Encephalopathy-Related Hospitalizations in Cirrhosis: Transition of Care and Closing the Revolving Door.

Cirrhosis is associated with substantial morbidity and mortality. Development of complications of cirrhosis, including hepatic encephalopathy (HE), portends poorer outcomes. HE is associated with hospital readmission, impaired patient and caregiver quality of life, risk of falls, and mortality. Guidelines recommend lactulose as first-line therapy for HE and rifaximin in combination with lactulose for reducing the risk of HE recurrence. Improving post-discharge outcomes, including readmissions, is an important aspect in the management of patients with HE. Approaches focused on improving management and prevention of HE, including properly titrating lactulose dosing, overcoming medication-related nonadherence, and incorporating rifaximin as therapy to reduce the risk of recurrence, as well as incorporating supportive care initiatives, may ease the transition from hospital to home. Strategies to decrease readmission rates include using hospital navigators, who can offer patient/caregiver education, post-discharge planning, and medication review; and involving pharmacists in post-discharge planning. Similarly, telemedicine offers providers the opportunity to monitor patients with HE remotely and improves outcomes. Providers offering transitional care management may be reimbursed when establishing contact with patients within 2 days post-discharge and conducting an outpatient visit within 7 days or 14 days. Several approaches have been shown to improve outcomes broadly in patients post-discharge and may also be effective for improving outcomes specifically in patients hospitalized with cirrhosis and HE, thus closing the revolving door on rehospitalizations in this population.

Multicenter, Double-Blind, Randomized Trial of Emricasan in Hepatitis C-Treated Liver Transplant Recipients With Residual Fibrosis or Cirrhosis.

Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P < 0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1 year and 82.4% at 3 years compared with 88.9% at 1 year and 80.4% at 3 years for non-NASH patients (log-rank P = 0.58 and P = 0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo.

BACKGROUND & AIMS: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study.

BACKGROUND & AIMS: Single-center studies have reported excellent outcomes of patients who underwent liver transplantation for hepatocellular carcinoma (HCC) after successful down-staging (reduction of tumor burden with local-regional therapy), but multi-center studies are lacking. We performed a multi-center study, applying a uniform down-staging protocol, to assess outcomes of liver transplantation and performed an intention to treat analysis. We analyzed factors associated with treatment failure, defined as dropout from the liver transplant waitlist due to tumor progression, liver-related death without transplant, or recurrence of HCC after transplant. METHODS: We performed a retrospective multi-center study of 187 consecutive adults with HCC enrolled in the down-staging protocol at 3 liver transplant centers in California (Region 5), from 2002 through 2012. All patients underwent abdominal imaging 1 month after each local-regional treatment, and at a minimum of once every 3 months. The primary outcome was probability of treatment failure. RESULTS: Liver transplantation was performed after successful down staging in 109 patients (58%). Tumor explant from only 1 patient had poorly differentiated grade and 7 (6.4%) had vascular invasion. Based on Kaplan-Meier analysis of data collected a median 4.3 years after liver transplantation, 95% of patients would survive 1 year and 80% of patients would survive 5 years; probabilities of recurrence-free survival were 95% and 87%, respectively. There were no center-specific differences in survival in the intention to treat analysis (P = .62), in survival after liver transplantation (P = .95), or in recurrence of HCC (P = .99). Patients were removed from the liver transplantation waitlist due to tumor progression in (n = 59; 32%) or liver-related death without liver transplantation (n = 9; 5%). Factors associated with treatment failure, based on multivariable analysis, were pre-treatment levels of alpha-fetoprotein (AFP) >1000 ng/mL (hazard ratio, 3.3; P < .001) and Child Pugh class B or C (hazard ratio, 1.6; P < .001). The probability of treatment failure at 2 years from the first down-staging procedure was 100% for patients with levels of AFP >1000 and Child Pugh class B or C vs 29.4% for patients with neither risk factor (P < .001). CONCLUSIONS: In a retrospective, multi-center study on HCC down staging under a uniform protocol, we found patients to have excellent outcomes following liver transplantation, with no center-specific effects. Our findings support application of the down-staging protocol on a broader scale. Patients with Child Pugh class B or C and AFP >1000 are unlikely to benefit from down staging.

Older Patients With Hepatocellular Carcinoma Have More Advanced Disease, Lower Rates of Treatment, and Lower Survival.

GOALS: To evaluate age-specific disparities in cancer stage at diagnosis, receipt of treatment, and survival among adults with hepatocellular carcinoma (HCC). BACKGROUND: HCC has become the fastest rising cause of cancer-related deaths in the United States. The aging population coupled with the rising incidence of HCC will result in an emerging cohort of older patients with HCC placing significant burden health care systems. STUDY: Using 2003 to 2011 Surveillance, Epidemiology, and End Results data, a US population-based cancer registry, we retrospectively evaluated age-specific disparities in cancer stage at diagnosis, receipt of treatment, and survival among adults with HCC. Multivariate logistic regression models evaluated HCC stage at diagnosis and HCC treatment received. Multivariate Cox proportional hazard models evaluated long-term survival. RESULTS: Compared with HCC patients below 50 years old, patients aged 70 years or older were less likely to have HCC within Milan criteria [odds ratio, 0.58; confidence interval (CI), 0.54-0.63; P<0.001]. Older age was also associated with significantly lower rates of receiving HCC treatment. Even after adjusting for stage of disease, patients aged 70 years or older had the lowest odds of receiving any HCC treatment compared with patients below 50 years old (odds ratio, 0.52; CI, 0.46-0.60; P<0.001). On multivariate Cox regression, HCC patients aged 70 years or older had significantly lower survival compared with patients below 50 years old (hazards ratio, 1.22; CI, 1.15-1.30; P<0.001). CONCLUSIONS: Among US adults with HCC, patients aged 70 years or older were less likely to have HCC within Milan criteria at diagnosis, less likely to receive any HCC treatment, and had significantly lower long-term survival.

Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network.

Recurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Achieving sustained virological response (SVR) with antiviral therapy improves survival. Because interferon (IFN)-based therapy has limited efficacy and is poorly tolerated, there has been rapid transition to IFN-free direct-acting antiviral (DAA) regimens. This article describes the experience with DAAs in the treatment of posttransplant genotype (GT) 1 HCV from a consortium of community and academic centers (Hepatitis C Therapeutic Registry and Research Network [HCV-TARGET]). Twenty-one of the 54 centers contributing to the HCV-TARGET consortium participated in this study. Enrollment criteria included positive posttransplant HCV RNA before treatment, HCV GT 1, and documentation of use of a simeprevir (SMV)/sofosbuvir (SOF) containing DAA regimen. Safety and efficacy were assessed. SVR was defined as undetectable HCV RNA 64 days or later after cessation of treatment. A total of 162 patients enrolled in HCV-TARGET started treatment with SMV+SOF with or without ribavirin (RBV) following LT. The study population included 151 patients treated with these regimens for whom outcomes and safety data were available. The majority of the 151 patients were treated with SOF and SMV alone (n = 119; 79%) or with RBV (n = 32; 21%), The duration of therapy was 12 weeks for most patients, although 15 patients received 24 weeks of treatment. Of all patients receiving SOF/SMV with or without RBV, 133/151 (88%) achieved sustained virological response at 12 weeks after therapy and 11 relapsed (7%). One patient had virological breakthrough (n = 1), and 6 patients were lost to posttreatment follow-up. Serious adverse events occurred in 11.9%; 3 patients (all cirrhotic) died due to aspiration pneumonia, suicide, and multiorgan failure. One experienced LT rejection. IFN-free DAA treatment represents a major improvement over prior IFN-based therapy. Broader application of these and other emerging DAA regimens in the treatment of posttransplant hepatitis C is warranted.

Race/Ethnicity-specific Disparities in Hepatocellular Carcinoma Stage at Diagnosis and its Impact on Receipt of Curative Therapies.

GOALS: To evaluate race/ethnicity-specific disparities in hepatocellular carcinoma (HCC) stage at diagnosis and how this impacts receiving curative therapies. BACKGROUND: HCC is a leading cause of morbidity and mortality worldwide. The highest incidence of HCC is seen among ethnic minorities in the United States. STUDY: Using the 2003-2011 Surveillance, Epidemiology, and End Results database and United Network of Organ Sharing, population-based registries for cancer and liver transplantation (LT) in the United States, race/ethnicity-specific cancer stage at diagnosis and treatment received among adults with HCC were evaluated. RESULTS: Compared with non-Hispanic whites, blacks had significantly more advanced HCC at diagnosis [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.10-1.30; P<0.001], whereas Asians were less likely to have advanced disease (OR, 0.87; CI, 0.80-0.94; P<0.001). Among patients with HCC meeting Milan criteria, Hispanics (OR, 0.64; 95% CI, 0.57-0.71; P<0.001) and blacks (OR, 0.67; 95% CI, 0.59-0.76; P<0.001) were significantly less likely to receive curative therapy (resection or LT), whereas Asians were more likely to receive curative therapy (OR, 1.22; 95% CI, 1.10-1.35; P<0.001) compared with non-Hispanic whites. However, Asians (OR, 0.49; 95% CI, 0.42-0.58; P<0.001) and Hispanics (OR, 0.51; 95% CI, 0.44-0.60; P<0.001) were less likely to receive LT. CONCLUSIONS: Among US adults with HCC, blacks consistently had more advanced stage at diagnosis and lower rates of receiving treatment. After correcting for cancer stage and evaluating the subset of patients eligible for curative therapies, blacks and Hispanics had significantly lower rates of curative HCC treatment.

Building the multidisciplinary team for management of patients with hepatocellular carcinoma.

Optimal care of the patient with hepatocellular carcinoma (HCC) necessitates the involvement of multiple providers. Because the patient with HCC often carries 2 conditions with competing mortality risks (cancer and underlying cirrhosis), no single provider is equipped to deal with all of these patients' needs adequately. Multidisciplinary teams (MDTs) have evolved to facilitate care coordination, reassessments of clinical course, and nimble changes in treatment plans required for this complex group of patients. Providers or sites that elect to manage patients with HCC thus are increasingly aware of the need to build their own MDT or communicate with an established one. The availability of new communication technologies, such as teleconferencing or teleconsultation, offers the possibility of MDT expansion into underserved or rural areas, as well as areas such as correctional facilities. Although the availability of resources for HCC patient care varies from site to site, construction of an MDT is possible in a wide spectrum of clinical practices, and this article suggests a blueprint for assembly of such collaboration. Research strategies are needed to explain how MDTs improve clinical outcomes so that MDTs themselves can be improved.

Pre-transplant utilization of sorafenib is not associated with increased complications after liver transplantation.

Hepatocellular carcinoma (HCC) is increasing in incidence, resulting in approximately 35% of orthotopic liver transplantation (OLT) performed each year. Sorafenib (SOR) is a multi-kinase inhibitor that is approved for the treatment of unresectable HCC. Concerns have been raised regarding the safety of SOR in patients undergoing major surgery. We retrospectively reviewed 79 consecutive patients with HCC receiving OLT. Patient data were compared for those who received SOR pre-OLT with those who did not. SOR was continued until time of transplant. During this time period, 15 patients received SOR pre-OLT and 64 did not. The two groups were similar with regards to demographic and clinical data. SOR patients were more likely to have larger tumors, more tumor nodules, and be outside of Milan criteria. The rate of recurrence of HCC was not different between the groups (13% in SOR group, 11% in no-SOR group). Surgical complications were not increased in patients receiving SOR prior to OLT. Survival rate was also similar between the two groups (median follow-up 19.7 months). In this small cohort of patients, use of SOR prior to liver transplantation does not confer an increased risk of surgical complications, even when continued until the day of surgery.

Clinical management and case reports for the treatment of hepatocellular carcinoma with sorafenib.

Hepatocellular carcinoma (HCC) is one of the most common solid organ malignancies worldwide, and its incidence is rising in industrialized nations. Sorafenib, an oral multikinase inhibitor, is effective for the treatment of advanced HCC, and is the only systemic drug indicated for the treatment of unresectable HCC. Patients with HCC often have cirrhosis due to viral infection, chronic alcohol consumption, or other causes of liver damage, resulting in reduced liver function of variable severity. Because of the heterogeneity of HCC cases, physicians must consider the benefits and risks associated with sorafenib treatment on a patient-by-patient basis. California Pacific Medical Center (PMC) has established a clinical protocol, discussed here, for treatment of HCC with sorafenib, and for management of treatment-associated adverse effects. In addition, 3 case reports are presented as examples of the use of sorafenib in patient populations not represented in the phase 3 trials: as an adjuvant treatment after a surgical procedure and as effective treatment for stabilizing recurrent and metastatic HCC.

Safety and efficacy of pharmacologic weight loss in patients with cirrhosis.

BACKGROUND: Obesity poses unique risks in patients with advanced liver fibrosis; however, given surgical risks of bariatric surgery in cirrhosis treatment recommendations are currently limited to lifestyle interventions. This study seeks to inform a potential treatment gap by describing the safety and efficacy of pharmacologic weight loss in patients with advanced liver disease. METHODS: A retrospective chart review of the electronic medical record was conducted for all patients in the Scripps Health system from 2005 to 2017 with established advanced liver fibrosis that were prescribed medications associated with weight loss. The primary outcome was safety as defined by the model for end-stage liver disease (MELD) score. Secondary outcomes included total body weight loss, reasons for medication discontinuation, medication adverse events, and hospitalization before and after medication initiation. RESULTS: Thirty-eight patients and 63 prescriptions were included in the final analysis. The most frequently prescribed medication associated with weight loss was metformin (63%, n = 24) followed by a GLP-1 agonist (39%, n = 15). There was no significant effect of weight-loss medication on MELD score (p > 0.18) or number of hospitalizations when adjusting for subject (p > 0.26). There was a significant adjusted mean weight loss of 2.2 kg (p < 0.02) following prescription of a medication associated with weight loss. The Federal Drug Administration-approved anti-obesity medications as a group resulted in a significant adjusted weight loss of 7.22 kg (p < 0.013). In a linear mixed-effects model accounting for subjects, weight loss was not independently associated with a change in MELD (t[51] = -1.972, p > 0.05). CONCLUSION: Pharmacologic weight loss in patients with advanced liver fibrosis appears feasible based on preliminary safety and efficacy outcomes in this study. Future prospective studies are warranted to evaluate a potential significant treatment gap in the management of obesity in this vulnerable population.

Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

Spotlight on Impactful Research: Utilization of Aspirin and Statin in Management of Coronary Artery Disease in Patients With Cirrhosis Undergoing Liver Transplant Evaluation.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-reading-frankul a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-interview-frenette an interview with the author Answer questions and earn https://www.wileyhealthlearning.com/Activity/7036138/disclaimerspopup.aspx.

To "be" or not to "be": that is the question.

Treatment guidelines currently consider hepatitis B early antigen (HBeAg) seroconversion to be the end point of treatment with oral antivirals for HBeAg-positive patients. However, it is clear that with the high HBeAg relapse rate (both natural and after treatment) along with the high rate of mixed infection and the prevalence of HBeAg-negative disease, HBeAg status can no longer be considered the most useful end point of treatment or the signal to initiate therapy. Hepatitis B surface antigen (HBsAg) loss or seroconversion is associated with a favorable prognosis in both HBeAg-positive and HBeAg-negative disease and should be considered the test result that, combined with undetectable HBV DNA, will trigger treatment cessation.