Impact of expanding hepatitis B treatment guidelines: A modelling and economic impact analysis.

BACKGROUND: Antiviral treatment in patients with chronic hepatitis B (CHB) may decrease the risk of hepatocellular carcinoma (HCC) and death. However, only 2.2% of CHB patients receive antiviral treatment globally. The complexity and strictness of the current clinical practice guidelines may limit expanding the treatment coverage for CHB. AIMS: To examine the impact of expanding treatment criteria on future disease burden in Korea, a hepatitis B virus (HBV) endemic country with high diagnostic rates. MATERIALS: Dynamic country-level data were used to estimate the HCC incidence, overall mortality and economic impact of three incremental scenarios compared to the base case in Korea through 2035. RESULTS: In 2020, 1,409,000 CHB cases were estimated, with the majority born before 1995. All scenarios assumed treating 70% of eligible individuals. The first scenario removed viral load restrictions in cirrhotic patients, which would avert 13,000 cases of HCC and save 11,800 lives. The second scenario, lowering the alanine aminotransferase (ALT) level restriction to the upper limit of the normal in non-cirrhotic patients, would avert 26,700 cases of HCC and save 23,300 lives. The last scenario removed the restriction by ALT and HBeAg in treating non-cirrhotic individuals with a viral load of ≥2000 IU/ml, which would avert 43,300 cases of HCC and save 37,000 lives. All scenarios were highly cost-effective. CONCLUSIONS: Simplifying and expanding treatment eligibility for CHB would save many lives and be highly cost-effective when combined with high diagnostic rates. These dynamic country-level data may provide new insights for their global application.

Cost-effectiveness of antiviral treatment in adult patients with immune-tolerant phase chronic hepatitis B.

OBJECTIVE: The cost-effectiveness of antiviral treatment in adult immune-tolerant (IT) phase chronic hepatitis B (CHB) patients is uncertain. DESIGN: We designed a Markov model to compare expected costs and quality-adjusted life-years (QALYs) of starting antiviral treatment at IT-phase ('treat-IT') vs delaying the therapy until active hepatitis phase ('untreat-IT') in CHB patients over a 20-year horizon. A cohort of 10 000 non-cirrhotic 35-year-old patients in IT-phase CHB (hepatitis B e antigen-positive, mean serum hepatitis B virus (HBV) DNA levels 7.6 log10 IU/mL, and normal alanine aminotransferase levels) was simulated. Input parameters were obtained from previous studies at Asan Medical Center, Korea. The incremental cost-effectiveness ratio (ICER) between the treat-IT and untreat-IT strategies was calculated. RESULTS: From a healthcare system perspective, the treat-IT strategy with entecavir or tenofovir had an ICER of US$16 516/QALY, with an annual hepatocellular carcinoma (HCC) incidence of 0.73% in the untreat-IT group. With the annual HCC risk ≥0.54%, the treat-IT strategy was cost-effective at a willingness-to-pay threshold of US$20 000/QALY. From a societal perspective considering productivity loss by premature death, the treat-IT strategy was extremely cost-effective, and was dominant (ICER <0) if the HCC risk was ≥0.43%, suggesting that the treat-IT strategy incurs less costs than the untreat-IT strategy. The most influential parameters on cost-effectiveness of the treat-IT strategy were those related with HCC risk (HBV DNA levels, platelet counts and age) and drug cost. CONCLUSION: Starting antiviral therapy in IT phase is cost-effective compared with delaying the treatment until the active hepatitis phase in CHB patients, especially with increasing HCC risk, decreasing drug costs and consideration of productivity loss.

Disparities in dietary quantity and quality between the two different types of Korean family of older adults living with spouses and living alone: using data from the 6th Korea National Health and Nutrition Examination Survey.

BACKGROUND/OBJECTIVES: This study was conducted to examine disparities in food and nutrient intakes based on family types identified among 1,856 participants who were the Korean elderly people in the 6th Korea National Health and Nutrition Examination Survey (KNHNES) excluding those who were currently practicing the diet therapy. SUBJECTS/METHODS: We separated the subjects into two groups: living alone (LA, n = 638) and living with a spouse (LS, n = 1,218). We also examined the disparities of dietary quantity and quality of those two groups using complex sampling design general linear regression analyses (CS GLM). RESULTS: In the LA group, there was a higher percentage of females and average age in LA group was higher than the participants in the LS group. Household income and education level were significantly lower in LA compared to those of LS. The frequencies of skipping meals were higher in LA. LA's food and nutrient intakes showed lower consumption of vegetables, fruits, seaweeds, and of most nutrients. Even after adjusting for the confounding factors, the consumption of vegetables, seaweeds, carbohydrates, potassium, riboflavin, and vitamin C showed lower in LA than LS. Moreover, LA's nutrient intake ratios compared to the KDRIs were lower which turned out to be similar to their nutrient intakes. CONCLUSIONS: These results show that dietary behavior and food intake of the elderly are associated with family types. Frequently skipping meals and less dietary variety are more common with elderly persons who were living alone. Therefore, it is necessary to integrate the supplementary food programs and nutrition education programs for the elderly living alone.

Magnetic Resonance Imaging Is Cost-Effective for Hepatocellular Carcinoma Surveillance in High-Risk Patients With Cirrhosis.

Ultrasonography (US) is generally recommended for the surveillance of hepatocellular carcinoma (HCC) in patients at risk. However, in patients with cirrhosis who have sufficiently high HCC incidence, surveillance using magnetic resonance imaging (MRI) with liver-specific contrast showed markedly higher sensitivity in detecting early-stage HCC than US. This study aimed to compare the cost-effectiveness of semiannual surveillance using MRI versus US in patients with compensated cirrhosis and to identify the population that would gain optimal cost-effectiveness through MRI surveillance. We designed a Markov model to compare the expected costs and quality-adjusted life-years (QALYs), between MRI and US, with a 20-year time horizon, from the health care system perspective. The starting age of the cohort was 50 years, and 71% had hepatitis B virus-associated cirrhosis. The cycle length was 6 months. Transition probabilities and costs were obtained mainly from a prospective cohort study (the PRIUS study, NCT01446666). Cost and effectiveness were discounted at 5%. An incremental cost-effectiveness ratio (ICER) was calculated and tested using sensitivity analyses. The cost-effectiveness analysis indicated that the use of MRI incurred $5,562 incremental costs, 0.384 incremental life-years (LYs), and 0.221 incremental QALYs compared to US. The annual HCC incidence was the most influential factor on the ICER. The ICERs were $14,474/LY and $25,202/QALY at an annual HCC incidence of 3%. When the HCC incidence rate was >1.81%, the ICER was below $50,000/QALY. With increased HCC incidence, MRI surveillance was acceptable as a cost-effective option, even with an increased MRI/US cost ratio. Conclusion: Semiannual surveillance using MRI with liver-specific contrast may be more cost-effective than US in patients with virus-associated compensated cirrhosis at sufficiently high HCC risk despite the higher test cost of MRI.

Longitudinal Assessment of Three Serum Biomarkers to Detect Very Early-Stage Hepatocellular Carcinoma.

We aimed to determine the surveillance performance of alpha-fetoprotein (AFP), lectin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), and their combinations for the early detection of hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow-up in a 1:4 ratio. Levels of AFP, AFP-L3, and DCP at the time of HCC diagnosis, month -6, and month -12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early-stage HCC (single <2 cm). AFP and AFP-L3 began to increase from 6 months before diagnosis of HCC in cases (P < 0.05), while they remained unchanged in controls. At HCC diagnosis, the area under the receiver operator characteristic curves (AUROCs) for AFP, AFP-L3, and DCP were 0.77, 0.73, and 0.71, respectively. Combining AFP and AFP-L3 showed a higher AUROC (0.83), while adding DCP did not further improve the AUROC (0.86). With the optimal cutoff values (AFP, 5 ng/mL; AFP-L3, 4%), the sensitivity and specificity of AFP and AFP-L3 combination were 79% and 87%, respectively. The sensitivity of ultrasonography was 48.6%, which was increased to 88.6% and 94.3% by adding AFP and AFP + AFP-L3, respectively. Conclusion: Among three biomarkers, AFP showed the best performance in discriminating HCC cases from controls; the AFP and AFP-L3 combination, adopting cutoff values (5 ng/mL and 4%, respectively), significantly improved the sensitivity for detecting HCC at a very early stage.

Performing Gadoxetic Acid-Enhanced MRI After CT for Guiding Curative Treatment of Early-Stage Hepatocellular Carcinoma: A Cost-Effectiveness Analysis.

OBJECTIVE: We determined the cost-effectiveness of two different diagnostic imaging strategies in guiding curative treatment of early-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We developed a decision analytic model using as its starting point a cohort of patients aged 55 years with early-stage HCC detected at dynamic multiphasic CT and with Child-Pugh class A cirrhosis. The model compared two strategies on the initial workup: conventional CT strategy using dynamic multiphasic CT only and gadoxetic acid-enhanced MRI strategy using additional gadoxetic acid-enhanced MRI after initial CT. A Markov cohort model simulated a cohort of patients after curative or adjuvant treatment, with follow-up over the remaining life expectancy. We analyzed mean life-years gain, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratio (ICER). To evaluate results, we performed one-way, two-way, and probabilistic sensitivity analyses. RESULTS: The life expectancies and QALY were 7.22 years and 5.08 for the conventional CT strategy and 7.79 years and 5.52 for the gadoxetic acid-enhanced MRI strategy, respectively. The expected costs were $99,770 for conventional CT and $105,025 for gadoxetic acid-enhanced MRI in the United States. The ICER with gadoxetic acid-enhanced MRI was $11,957, as opposed to that with conventional CT, which was lower than the cost-effectiveness threshold of $50,000/QALY. One-way, two-way, and probabilistic sensitivity analyses showed unchanged results over an acceptable range. CONCLUSION: Gadoxetic acid-enhanced MRI after CT is cost-effective for detecting additional HCC in patients with early-stage HCC who can undergo curative treatment (besides liver transplantation). The cost-effectiveness of gadoxetic acid-enhanced MRI may be considered in the management of patients with early-stage HCC during staging.

The impact of hepatitis C virus outside the liver: Evidence from Asia.

Between 80 and 115 million people worldwide are chronically infected with hepatitis C virus, with 60%-90% of these being undiagnosed. Untreated chronic hepatitis C (CHC) is associated with progressive liver disease, cirrhosis, hepatocellular carcinoma and liver-related mortality. A number of extrahepatic manifestations are also reported in CHC patients, further adding to the burden of the disease. CHC also impacts patients in terms of lower health-related quality of life, higher levels of fatigue and reduced productivity. Furthermore, the later stages of disease are costly for both healthcare systems and society. Pegylated-interferon (PEG-IFN)+ribavirin (RBV), for many years the mainstay of treatment, leads to sustained virological response (SVR) in 40%-70% of patients. However, a substantial number of patients are ineligible for treatment, and many patients fail to achieve SVR with this regimen. Furthermore, PEG-IFN+RBV leads to impairment of patient-reported outcomes during treatment, and most patients suffer from adverse events, associated with poor adherence, treatment discontinuation and treatment failure. The approval of second-generation direct-acting antivirals (DAAs) has revolutionized the treatment of CHC patients. All-oral, PEG-IFN and RBV-free regimens have higher efficacy rates, shorter treatment durations, fewer adverse events, higher adherence rates and improvement in PROs from as early as Week 4, compared to PEG-IFN+RBV regimens. The aim of this article is to review the evidence for HCV infection as a systemic disease, summarizing the impact of hepatitis C and its treatments on clinical, patient and economic outcomes, with a focus on data from Asia and Japan specifically.

Validation and reappraisal of the assessment for retreatment with transarterial chemoembolization score for unresectable non-metastatic hepatocellular carcinoma in a hepatitis b virus-endemic region.

OBJECTIVES: To validate and reappraise the Assessment for Retreatment with Transarterial chemoembolization (ART) score comprising three parameters (>25 % increase in aspartate aminotransferase [AST], increase in Child-Pugh score and tumour response), determined prior to subsequent transarterial chemoembolization (TACE). METHODS: Enrolled patients were diagnosed with unresectable non-metastatic hepatocellular carcinoma and underwent multiple TACEs between June 2006 and December 2007 (N = 153). Subgroupings were classified according to the established cut-off (≤1.5 vs. ≥2.5). Survival analysis using the Kaplan-Meier curve was performed. RESULTS: The original ART score dichotomized patients according to their overall survival (P = 0.004). We found several patients who actually survived longer than others were assigned to a poor prognostic group due to the AST component. Parameter estimates for AST obtained from our analysis were much lower than the original version (0.5 vs. 2.1). We adjusted the component according to the value of our parameter estimates, and patients with >25 % AST increase received 1.0 point. After this modification, patients assigned to the favourable prognostic group were more likely to have a better survival outcome (median 23.9 vs. 12.2 months, P < 0.001). CONCLUSIONS: In hepatitis B virus-endemic regions, the ART score is valid and can better predict post-TACE survival after the AST component is modified. KEY POINTS: • The ART score was validated in a HBV-endemic region. • The modified ART score improved prognostic performance by reappraising the AST component. • The modified ART score helps physicians make decisions for further TACE.

A review of the burden of hepatitis C virus infection in China, Japan, South Korea and Taiwan.

Hepatitis C virus (HCV) infection is associated with substantial clinical and economic burden and is an important public health issue in Asia. The objective of this review was to characterize HCV epidemiology and related complications in China, Japan, South Korea and Taiwan. A search of electronic databases and conference abstracts identified 71 potentially relevant articles. Of those, 55 were included in the epidemiology review and 9 in the review of HCV-related complications. HCV prevalence in the general population was 1.6% in China, 0.6-0.9% in Japan, 0.6-1.1% in South Korea and 1.8-5.5% in Taiwan. Prevalence was higher for injecting drug users (48-90%) and those with human immunodeficiency virus coinfection (32-85%) and was lower for blood donors (<1%). Annual incidence of HCV in China was 6.01 per 100,000. HCV genotype 1b was associated with the highest incidence of hepatocellular carcinoma (HCC). Five-year survival for patients with liver cirrhosis was 73.8%, decreasing to 39.2% following liver transplantation; the majority of deaths were attributable to HCC. Limitations were that the majority of studies included in the epidemiology review were small, regional studies conducted in specific populations, and there was an absence of large population-based studies. Thus, estimates may not be representative of the epidemiology of HCV for each country. The prevalence HCV in China and HCV incidence in the Asian region remain largely unknown, and they are likely underestimated. Further epidemiologic and clinical data are needed to provide more precise estimates for use by public health agencies.

Assessment of current criteria for primary nonresponse in chronic hepatitis B patients receiving entecavir therapy.

UNLABELLED: A primary nonresponse to oral drugs against hepatitis B virus (HBV) is a generally accepted criterion for interrupting treatment. We investigated whether the concept of primary nonresponse suggested by current American (AASLD) and European (EASL) guidelines is appropriate for treatment with entecavir (ETV). The study included 1,254 treatment-naïve patients who had pretreatment HBV DNA levels of >2,000 IU/mL and received ETV 0.5 mg/day for over 6 months. "Primary nonresponse" was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD and as a <1 log drop after 3 months by EASL. The cumulative probability of virological response (VR; HBV DNA of <15 IU/mL) was compared in patients with and without primary nonresponse. Median time to achieve VR was significantly shorter in primary responders by AASLD than nonresponders (12 versus 24 months; P = 0.004), but the cumulative probability of achieving a VR at 54 months was similar in the two groups (95.8% versus 100%). Time to achieve a VR and cumulative probability of VR over time did not differ between primary responders and nonresponders by EASL. On-treatment virological breakthrough occurred in 18 patients with a cumulative rate of 5.6% at 72 months. ETV resistance was detected in 13 of these 18 patients (72.2%), who were all classified as primary responder according to both guidelines. CONCLUSION: Long-term ETV therapy generally leads to a VR in treatment-naïve patients, although the time to achieve it is delayed in primary nonresponders. The current recommendation to change therapy in primary nonresponders needs to be modified to reflect drug differences in antiviral potency and resistance risk.

A novel estimation of the relative economic value in terms of different chronic hepatitis B treatment options.

BACKGROUND: Prescribers, payors and healthcare decision-makers are increasingly examining the value of treatments. This study aims at analyzing economic value of chronic hepatitis B (CHB) treatment options, which are available in Korea. METHODS: CHB infection was simulated using a health-state transition model with disease states defined as mild disease (Ishak F0/F1), fibrosis (F2/F3/F4), advanced fibrosis/cirrhosis (>F4), and complicated disease states (decompensated cirrhosis, hepatocellular carcinoma, liver transplant and death) based on available natural history data. The value of treatment-specific attributes on disease progression/regression was estimated based on published data in terms of events and costs avoided. 5-year treatment duration was assumed except for treatment initiation. Primary model output is the estimated cost savings of entecavir per patient per day of treatment versus the comparator in question for a given CHB patient. RESULTS: The simulation of treating with entecavir versus no treatment predicted improved clinical outcomes for entecavir-treatment patients. In the long term, these clinical benefits translate into cost savings of $3.10 per day of treatment. In naive patient treatment, daily cost savings of using entecavir versus lamivudine or telbivudine was estimated at $2.89 and $1.72, respectively. In the case of suboptimal responders who pre-treated with lamivudine, daily cost saving for patients switching to entecavir was $1.38 per day of treatment compared to patients maintaining on lamivudine. CONCLUSIONS: Entecavir exhibits characteristics of a favourable CHB treatment, which directly translates into economic and therapeutic value as opposed to either no treatment or alternative strategies.

Continuous peritransplant assessment of consciousness using bispectral index monitoring for patients with fulminant hepatic failure undergoing urgent liver transplantation.

BACKGROUND: Rapid deterioration of consciousness is a critical situation for patients with fulminant hepatic failure (FHF). Bispectral (BIS) index was derived from electroencephalography parameters, primarily to monitor the depth of unconsciousness. AIM: To assess the usability of peritransplant BIS monitoring in patients with FHF. METHODS: A prospective study using peritransplant BIS monitoring was performed in 26 patients with FHF undergoing urgent liver transplantation (LT). RESULTS: Pre-transplant Child-Pugh score was 12.2 +/- 1.0; model for end-stage liver disease score was 32.4 +/- 4.4; Glasgow coma score (GCS) was 9.9 +/- 1.3; and BIS index was 44.0 +/- 6.7. Pre-transplant sedation significantly decreased BIS index. After LT, all patients having endotracheal intubation recovered consciousness within one to three d and showed progressive increase in BIS index, which appeared slightly earlier and was more evident than the increase in derived GCS score. There was a significant correlation between BIS index and derived GCS scores (r(2) = 0.648). Timing of eye opening to voice was matched with BIS index of 66.3 +/- 10.4 and occurred 12.7 +/- 8.3 h after passing BIS index of 50. CONCLUSION: These results suggest that BIS monitoring is a non-invasive, simple, easy-to-interpret method, which is useful in assessing peritransplant state of consciousness. BIS monitoring may therefore be a useful tool during peritransplant intensive care for patients with FHF showing hepatic encephalopathy.

Assessment of the efficacy of reducing peginterferon alpha-2a and ribavirin dose on virologic response in Koreans with chronic hepatitis C.

BACKGROUND/AIMS: The virologic response of Koreans to combination therapy for chronic hepatitis C is similar to westerns; however, dose modification occurs more frequently in Koreans. We evaluated the rates of peginterferon alpha-2a and ribavirin dose modifications and their effect on the virologic response in Koreans. METHODS: Patients with detectable HCV RNA and enrolled from multicenters were treated with peginterferon alpha-2a (180 microg/week) and ribavirin (800 mg/day) for 24 weeks (genotype non-1, n=37) or peginterferon alpha-2a (180 microg/week) and ribavirin (1,000-1,200 mg/day) for 48 weeks (genotype 1, n=55). RESULTS: Early virologic response (EVR) and sustained virologic response (SVR) were 77.2% (genotype 1, 75%; non-1, 81%) and 66.3% (genotype 1, 56%; non-1, 81%), respectively. The frequency of dose modification was 32.6% within the first 12 weeks and 52.2% during the entire treatment period. No difference was found in SVR regardless of dose modification. However, the SVR for patients using >or=80% of the peginterferon dose was significantly higher than for those using <80% (81.3 vs. 50.0%, p=0.007), despite varying ribavirin doses. No difference was found in SVR regardless of whether the ribavirin dose was <80% or not. These results did not change based on genotype. CONCLUSIONS: We suggest that using at least 80% of the peginterferon alpha-2a dose in Koreans not only maintains SVR but also reduces drug side effects during the entire treatment period. A lower dose of ribavirin may be as efficacious as a standard dose.

The global impact of hepatic fibrosis and end-stage liver disease.

Hepatic fibrosis is an integral part in the progression of chronic liver disease, ultimately leading to cirrhosis and hepatocellular carcinoma. Globally, alcohol consumption, hepatitis B (HBV) and hepatitis C (HCV) have been the main causes of cirrhosis. More recently, the increasing prevalence of obesity and the metabolic syndrome has resulted in increasing incidence of cirrhosis secondary to nonalcoholic fatty liver disease (NAFLD), especially in developed countries. Chronic liver disease and cirrhosis are important causes of morbidity and mortality in the world. Moreover, the burden of chronic liver disease is projected to increase, due in part to the increasing prevalence of end-stage liver disease and HCC secondary to NAFLD and HCV.