Cost-effectiveness modelling of birth and infant dose vaccination against hepatitis B virus in Ontario from 2020 to 2050.

BACKGROUND: The World Health Organization recommends universal birth dose vaccination for hepatitis B virus (HBV), yet only 3 provinces and territories in Canada provide birth dose vaccination, and Canadian-born children in Ontario are acquiring HBV before adolescent vaccination. We sought to determine whether birth and/or infant HBV vaccination is cost-effective. METHODS: We used a dynamic HBV model that incorporates population by year, disease stage, sex and the influence of immigration to quantify the disease and economic burden of chronic HBV infection in Ontario from 2020 to 2050. We compared 4 vaccination scenarios, which included a birth dose vaccine and variations of the 2 subsequent doses (either alone or as a part of the hexavalent vaccine) and a hexavalent-only strategy in infancy with the current adolescent vaccination strategy. Our costing estimates were based on values from 2020. RESULTS: All 4 infant vaccination approaches prevented an additional 550-560 acute and 160 chronic pediatric HBV infections from 2020 to 2050 compared with adolescent vaccination. Whereas birth dose could be cost-effective, incorporating vaccination into a hexavalent vaccine was cost saving. By 2050, the hexavalent approach led to $428 000 in cost savings per disability-adjusted life years averted. INTERPRETATION: At the current prevalence in Ontario, a switch to birth dose or infant dose will be cost-effective or even cost saving. Introducing any form of infant HBV immunization in Ontario will prevent acute and chronic pediatric HBV infections.

Internal medicine hospitalisations and liver disease: a comparative disease burden analysis of a multicentre cohort.

BACKGROUND: Liver disease is an increasing burden on population health globally. AIMS: To characterise burden of liver disease among general internal medicine inpatients at seven Toronto-area hospitals and compare it to other common medical conditions. METHODS: Data from April 2010 to October 2017 were obtained from hospitals participating in the GEMINI collaborative. Using these cohort data from hospital information systems linked to administrative data, we defined liver disease admissions using most responsible discharge diagnoses categorised according to international classification of diseases, 10th Revision-enhanced Canadian version (ICD-10-CA). We identified admissions for heart failure, chronic obstructive pulmonary disease (COPD) and pneumonia as comparators. We calculated standardised mortality ratios (SMRs) as the ratio of observed to expected deaths. RESULTS: Among 239 018 discharges, liver disease accounted for 1.7% of most responsible discharge diagnoses. Liver disease was associated with marked premature mortality, with SMR of 8.84 (95% CI 8.06-9.67) compared to 1.06 (95% CI 0.99-1.12) for heart failure, 1.05 (95% CI 0.96-1.15) for COPD and 1.28 (95% CI 1.20-1.37) for pneumonia. The majority of deaths were among patients younger than 65 years (57.7%) compared to 3.3% in heart failure, 5.6% in COPD and 10.7% in pneumonia. Liver disease patients presented with worse Laboratory-Based Acute Physiology Scores, were more frequently admitted to the intensive care unit (14.4%), incurred higher average total costs (median $6723 CAD), had higher in-hospital mortality (11.4%), and were more likely to be a readmission from 30 days prior (19.8%). Non-alcoholic fatty liver disease admissions increased from 120 in 2011-2012 to 215 in 2016-2017 (P < 0.01). CONCLUSION: In Canada's largest urban centre, liver disease admissions resulted in premature morbidity and mortality with higher resource use compared to common cardio-respiratory conditions. Re-evaluation of approaches to caring for inpatients with liver disease is timely and justified.

Patient Knowledge, Beliefs and Barriers to Hepatitis B Care: Results of a Multicenter, Multiethnic Patient Survey.

BACKGROUND: A greater understanding of the determinants of health behavior among those with and at-risk of chronic hepatitis B virus (HBV) infection is needed for effective design and implementation of public health initiatives. AIMS: To determine factors associated with (1) willingness to accept HBV antiviral treatment and (2) satisfaction with provider communication regarding HBV care in a diverse cohort of HBV-infected patients. METHODS: Using a multifaceted model of health behavior, the Health Behavior Framework, we conducted a comprehensive assessment of knowledge, attitudes, beliefs, and barriers to HBV care. RESULTS: We enrolled 510 patients, with mean age 46 years; 53.1% men; and 71.6% Asian or Hawaiian/Pacific Islander. Patients were knowledgeable about HBV infection, but one-fifth did not think that HBV was a treatable disease; over a quarter felt it was so common among family and friends that it did not concern them, and less than half of patients believed they were likely to have liver problems or transmit HBV to others during their lifetime. Perceived susceptibility to disease risk was the only independent predictor of willingness to accept HBV treatment (ß = 0.23, p = 0.0005), and contrary to expectations, having a doctor that speaks the same language was predictive of lower patient satisfaction with provider communication about their HBV care (ß = - 0.65, p < 0.0001). CONCLUSIONS: Patients with greater perceived susceptibility to the health consequences of HBV infection are more likely to accept treatment, and patient-provider language concordance impacts patient satisfaction with communication regarding HBV care in an unexpected direction.

Prenatal hepatitis B screening, and hepatitis B burden among children, in Ontario: a descriptive study.

BACKGROUND: Ontario is 1 of 5 provinces that immunize adolescents for hepatitis B virus (HBV), despite the World Health Organization recommendation for universal birth dose vaccination. One rationale for not vaccinating at birth is that universal prenatal screening and related interventions prevent vertical transmission. The aims of our study were to evaluate the uptake and epidemiology of prenatal HBV screening, and to determine the number of children in Ontario with a diagnosis of HBV before adolescent vaccination. METHODS: We extracted data from ICES, Public Health Ontario and Better Outcomes & Registry Network (BORN) Ontario databases. We assessed prenatal screening uptake and prevalence of prenatal hepatitis B surface antigen (HBsAg) from 2012 to 2016, as well as subsequent hepatitis B e-antigen (HBeAg) and HBV DNA testing and percent positivity. We used age and region to subcategorize the results. In a separate unlinked analysis, we evaluated the number of children positive for HBV aged 0-11 years who were born in Ontario from 2003 to 2013. RESULTS: From 2012 to 2016, 93% of pregnant women were screened for HBV, with an HBsAg prevalence of 0.6%. Prevalence of HBsAg increased with age, peaking at older than 45 years at 3%. North Toronto had the highest overall prevalence of 1.5%, whereas northern Ontario had the lowest. Of women who were HBsAg positive, HBeAg and HBV DNA tests were subsequently ordered in 13% and 38%, respectively. Of children born in Ontario between 2003 and 2013, 139 of 23 759 tested positive for HBV. INTERPRETATION: Prenatal HBV screening is not universal and subsequent evaluation is poor, limiting optimal intervention and possibly contributing to some Ontario-born children being given a diagnosis of HBV before age 12 years. These findings underscore the limitations of the province's adolescent vaccination strategy.

Liver safety assessment in clinical trials of new agents for chronic hepatitis B.

Investigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)-infected hepatocytes are intended to induce a durable off-treatment clearance of hepatitis B surface antigen (HBsAg) (referred to as functional cure). The aim of this paper was to highlight challenges in interpreting liver safety data in clinical trials of these agents when given alone or in combination regimens. The incidence, grading and management of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed along with a summary of serum ALT flares observed during the registration trials for peginterferon and nucleos(t)ide reverse transcriptase inhibitors. Recommendations regarding the detection, management and interpretation of liver safety biomarker data in future clinical trials as well as suggested inclusion and exclusion criteria for phase 1/2 vs phase 3 studies are provided. Criteria to help classify liver safety signals as being due to the intended therapeutic response, emergence of drug-resistant HBV virions, or idiosyncratic drug-induced liver injury are provided along with a review of the role of an expert hepatic adjudication panel in assessing a compound's hepatotoxicity profile. Finally, an algorithmic approach to the differential diagnosis and recommended medical evaluation and management of individual clinical trial patients that develop a liver safety signal is provided along with the rationale to collect and test research blood samples for future mechanistic studies.

Cost Effectiveness of Hepatocellular Carcinoma Surveillance After a Sustained Virologic Response to Therapy in Patients With Hepatitis C Virus Infection and Advanced Fibrosis.

BACKGROUND & AIMS: Hepatitis C virus (HCV)-related cirrhosis increases the risk for hepatocellular carcinoma (HCC). After a sustained virologic response (SVR) to anti-HCV therapy, the risk of HCC is reduced but not eliminated. Recent developments in antiviral therapy have increased rates of SVR markedly. Guidelines recommend indefinite biannual ultrasound surveillance after SVR for patients with advanced fibrosis before treatment. Surveillance for HCC is cost effective before anti-HCV treatment; we investigated whether it remains so after SVR. METHODS: We developed a Markov model to evaluate the cost effectiveness of biannual or annual HCC ultrasound surveillance vs no surveillance in 50-year-old patients with advanced fibrosis after an SVR to anti-HCV therapy. Parameter values were obtained from publications and expert opinions. Primary outcomes were quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratios (ICERs). RESULTS: With a constant 0.5% annual incidence of HCC, biannual and annual surveillance resulted in ICERs of $106,792 and $72,105 per QALY, respectively, with high false-positive rates. When surveillance was limited to patients with cirrhosis, but not F3 fibrosis, biannual surveillance likely was cost effective, with ICERs of $48,729 and $43,229 per QALY after treatment with interferon and direct-acting antiviral agents, respectively. In patients with F3 fibrosis, the incidence of HCC was 0.3% to 0.4% per year, leading to an ICER of $188,157 per QALY for biannual surveillance. If HCC incidence increases with age, surveillance becomes more cost effective but remains below willingness-to-pay thresholds only for patients with cirrhosis or with pretreatment aspartate aminotransferase to platelet ratio index greater than 2.0 or FIB-4 measurements greater than 3.25. Sensitivity analyses identified HCC incidence and transition rate to symptomatic disease without surveillance as factors that affect cost effectiveness. CONCLUSIONS: In a Markov model, we found HCC surveillance after an SVR to HCV treatment to be cost effective for patients with cirrhosis, but not for patients with F3 fibrosis.

Publicly Funded Oral Chronic Hepatitis B Treatment Patterns in Ontario over 16 Years: An Ecologic Study.

BACKGROUND: Reimbursement for the use of hepatitis B virus (HBV) treatments has not been previously reported for public payers. OBJECTIVE: To describe the number of users and total cost of HBV treatments over the last 16 years among residents of Ontario, Canada, who were covered by the public drug program. METHODS: We conducted a repeated cross-sectional study for HBV treatments reimbursed by the public drug program in Ontario from January 1, 2000, to December 31, 2015. We projected total spending to 2020 based on current utilization trends. RESULTS: HBV drug users per year increased 30-fold, from 132 users in 2000 to 4,035 users in 2015. Total spending on HBV treatments increased 150-fold, from $136,368 annually in 2000 to $21.0 million in 2015. The spending on HBV agents is projected to increase by 65%, with an estimated drug cost of $34.6 million by 2020. CONCLUSIONS: Although not reimbursed as first-line therapy, tenofovir disoproxil fumarate has become the most commonly reimbursed HBV treatment and was associated with an increase in HBV treatment use and total spending. Results of this study found that rapid growth of HBV treatments led to a sustained increase in spending for public payers in Ontario. DISCLOSURES: This study was funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC) and Ontario Strategy for Patient-Orientated Research (SPOR) Support Unit, which is supported by the Canadian Institutes of Health Research and the Province of Ontario. This study was also supported by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario MOHLTC. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors and not necessarily those of CIHI. Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. Janssen has received research support, consulting, and/or speaking fees from Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, Arbutus, Janssen, and MedImmune. No other authors have any conflicts of interest to declare.

Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients.

BACKGROUND & AIMS: While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. METHODS: Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. RESULTS: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. CONCLUSIONS: APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy.

In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01% to 1.4% in non-cirrhotic patients, and from 0.9% to 5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but this was only observed in some studies. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value.

Assessment of the effect of ribavirin on myeloid and plasmacytoid dendritic cells during interferon-based therapy of chronic hepatitis B patients.

The combination of ribavirin and peginterferon is the current standard of anti-viral treatment for chronic HCV patients. However, little is known on the mode of action of ribavirin in the anti-viral treatment of HCV patients. To investigate the immunomodulatory mechanism of ribavirin, we studied peginterferon alone versus peginterferon and ribavirin in chronic HBV patients. The addition of ribavirin did not affect the number of myeloid dendritic cells (mDC) or plasmacytoid dendritic cells (pDC), nor did it enhance T-helper-1 cell activity or T-cell proliferation. In contrast, it increased upregulation of activation markers on mDC and pDC, which was sustained throughout treatment. However, the addition of ribavirin had no effect on IFNα production by pDC. Our findings demonstrate that, although ribavirin does not lead to a viral load decline, in vivo treatment with ribavirin affects the activation of pDC and mDC in chronic HBV patients.

Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C.

BACKGROUND: Fibrosis determines prognosis and management in patients with chronic hepatitis B and C (CHB and CHC). Transient elastography (TE) is a promising non-invasive method to assess fibrosis. We prospectively studied the performance of TE compared to histology and also whether there are differences between CHB and CHC. Only large biopsies (≥ 25 mm) were used. METHODS: We included 241 patients with CHB (n = 125) and CHC (n = 116), of whom we acquired 257 liver biopsies, all preceded by elastography. We correlated liver stiffness with fibrosis stage according to the METAVIR system, inflammation (Histology Activity Index), steatosis and iron. The impact of gender, age, body mass index, alcohol, alanine aminotransferase levels, platelet count, viral load and genotype on liver stiffness was evaluated. RESULTS: The AUROC's for F ≥ 2 were 0.85 for CHB and 0.76 for CHC. AUROC's for F ≥ 3 were 0.91 for CHB and 0.87 for CHC and 0.90 and 0.91 for F4 for CHB and CHC respectively. For F ≥ 2 the cut-off value was 6.0 kPa for CHB and 5.0 kPa for CHC. The cut-off values for ≥ F3 were 9.0 and 8.0 kPa for CHB and CHC, respectively, and 13.0 kPa for F4 in both CHB and CHC patients. Besides inflammation, all other remaining factors do not influence liver stiffness. CONCLUSION: For the diagnosis of fibrosis stages F ≤ 2 TE is suboptimal, and inflammation may induce higher values. For stages F ≥ 3 TE performance is good and equal in both CHB and CHC patients.