A province-by-province cost-effectiveness analysis and budget impact analysis of one-time birth cohort screening of hepatitis C virus (HCV) infection in Canada.

Managing chronic hepatitis C is challenging, as the majority of those infected are asymptomatic. Therefore, to ensure treatments are administered before the onset of severe complications, screening is important. In Canada, uncertainty regarding the cost-effectiveness and budget impact of screening has led to conflicting recommendations. The objective of this study is to estimate the cost-effectiveness and budget-impact of one-time HCV screening. A state-transition model was developed to evaluate the cost-effectiveness and budget-impact between a risk-based screening strategy (current-practice) and a one-time screening strategy on three different birth-cohorts. Cost and prevalence data were obtained from administrative data. Progression and utility data were based on recent systematic reviews. We used a provincial payer-perspective, life-time time-horizon and a 1.5% discount rate for the cost-effectiveness analysis, and used a 10-year time-horizon and no discounting for the budget-impact analysis. One-time screening strategy would cost more and provide more health benefits than the risk-based screening for all birth cohorts. For those born after 1964, the incremental-cost-effectiveness-ratio (ICER) per quality-adjusted-life-year (QALY) of screening versus current-practice varied from $27,422/QALY to $42,191/QALY across different provinces. One-time screening of the cohort would cost an additional $2 million to $236 million across different provinces. For those born 1945-1964, the ICER of screening versus current-practice varied from $35,217/QALY to $48,197/QALY across different provinces. For the cohort born before 1945, the ICER of screening versus current-practice was not cost-effective at a willingness-to-pay threshold of $50,000/QALY across all provinces. Our cost-effectiveness analysis suggests that a one-time HCV screening program for those born after 1945 is cost-effective. Considering the budget impact relative to other funded recommended health services and technologies, HCV screening could be considered affordable.

Health care costs associated with chronic hepatitis C virus infection in Ontario, Canada: a retrospective cohort study.

BACKGROUND: High-quality estimates of health care costs are required to understand the burden of illness and to inform economic models. We estimated the costs associated with hepatitis C virus (HCV) infection from the public payer perspective in Ontario, Canada. METHODS: In this population-based retrospective cohort study, we identified patients aged 18-105 years diagnosed with chronic HCV infection in Ontario from 2003 to 2014 using linked administrative data. We allocated the time from diagnosis until death or the end of follow-up (Dec. 31, 2016) to 9 mutually exclusive health states using validated algorithms: no cirrhosis, no cirrhosis (RNA negative) (i.e., cured HCV infection), compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, both decompensated cirrhosis and hepatocellular carcinoma, liver transplantation, terminal (liver-related) and terminal (non-liver-related). We estimated direct medical costs (in 2018 Canadian dollars) per 30 days per health state and used regression models to identify predictors of the costs. RESULTS: We identified 48 239 patients with chronic hepatitis C, of whom 30 763 (63.8%) were men and 35 891 (74.4%) were aged 30-59 years at diagnosis. The mean 30-day costs were $798 (95% confidence interval [CI] $780-$816) (n = 43 568) for no cirrhosis, $661 (95% CI $630-$692) (n = 6422) for no cirrhosis (RNA negative), $1487 (95% CI $1375-$1599) (n = 4970) for compensated cirrhosis, $3659 (95% CI $3279-$4039) (n = 3151) for decompensated cirrhosis, $4238 (95% CI $3480-$4996) (n = 550) for hepatocellular carcinoma, $8753 (95% CI $7130-$10 377) (n = 485) for both decompensated cirrhosis and hepatocellular carcinoma, $4539 (95% CI $3746-$5333) (n = 372) for liver transplantation, $11 202 (95% CI $10 645-$11 760) (n = 3201) for terminal (liver-related) and $8801 (95% CI $8331-$9271) (n = 5278) for terminal (non-liver-related) health states. Comorbidity was the most significant predictor of total costs for all health states. INTERPRETATION: Our findings suggest that the financial burden of HCV infection is substantially higher than previously estimated in Canada. Our comprehensive, up-to-date cost estimates for clinically defined health states of HCV infection should be useful for future economic evaluations related to this disorder.

Estimating chronic hepatitis C prevalence in British Columbia and Ontario, Canada, using population-based cohort studies.

Patients identified as having chronic hepatitis C (CHC) infection can be effectively and rapidly treated using direct-acting antiviral agents. However, there remains a substantial burden of subclinical undetected infection. This study estimates the prevalence and undiagnosed proportion of CHC in British Columbia (BC) and Ontario, Canada, using a model-based approach, informed by provincial population-level health administrative data. A two-step approach was used: Step 1) Two population-based retrospective analyses of administrative health data for a cohort of British Columbians and a cohort of Ontarians with CHC were conducted to generate population-level statistics of CHC-related health events; Step 2) using a validated natural history model of hepatitis C virus (HCV) infection, the historical prevalence of CHC was back-calculated from the data collected in Step 1. Our retrospective study found that, in BC and Ontario, the number of newly diagnosed CHC cases is declining yearly while the complications of the disease are increasing yearly. BC had a 2014 CHC prevalence of 1.04% (95% CI: 0.84%-1.44%), with 33.3% (95% CI: 25.5%-42.0%) of CHC cases undiagnosed. Ontario had a 2014 CHC prevalence of 0.91% (95% CI: 0.83%-1.02%) with 36.0% (95% CI: 31.2%-38.9%) of CHC cases undiagnosed. Our study offers robust estimates based on the integration of a validated natural history model with population-level health administrative data on HCV-related events, which can provide vital evidence for policymakers to develop appropriate policies to achieve elimination targets. Our approach can also be applied to produce robust region-specific estimates in other countries.

The UGTome: The expanding diversity of UDP glycosyltransferases and its impact on small molecule metabolism.

The UDP glycosyltransferase (UGT) superfamily of enzymes is responsible for the metabolism and clearance of thousands of lipophilic chemicals including drugs, toxins and endogenous signaling molecules. They provide a protective interface between the organism and its chemical-rich environment, as well as controlling critical signaling pathways to maintain healthy tissue function. UGTs are associated with drug responses and interactions, as well as a wide range of diseases including cancer. The human genome contains 22 UGT genes; however as befitting their exceptionally diverse substrate ranges and biological activities, the output of these UGT genes is functionally diversified by multiple processes including alternative splicing, post-translational modification, homo- and hetero-oligomerization, and interactions with other proteins. All UGT genes are subject to extensive alternative splicing generating variant/truncated UGT proteins with altered functions including the capacity to dominantly modulate/inhibit cognate full-length forms. Heterotypic oligomerization of different UGTs can alter kinetic properties relative to monotypic complexes, and potentially produce novel substrate specificities. Moreover, the recently profiled interactions of UGTs with non-UGT proteins may facilitate coordination between different metabolic processes, as well as providing opportunities for UGTs to engage in novel 'moonlighting' functions. Herein we provide a detailed and comprehensive review of all known modes of UGT functional diversification and propose a UGTome model to describe the resulting expansion of metabolic capacity and its potential to modulate drug/xenobiotic responses and cell behaviours in normal and disease contexts.

Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. METHODS: We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. RESULTS: Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69-25 and 12.5, 95% CI 4.35-33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55-33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04-8.84 and 3.33, 95% CI 1.16-10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38-42.7 and 11.71, 95% CI 1.03-150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. CONCLUSIONS: Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms.

UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.

Cooperative Regulation of Intestinal UDP-Glucuronosyltransferases 1A8, -1A9, and 1A10 by CDX2 and HNF4α Is Mediated by a Novel Composite Regulatory Element.

The gastrointestinal tract expresses several UDP-glucuronosyltransferases (UGTs) that act as a first line of defense against dietary toxins and contribute to the metabolism of orally administered drugs. The expression of UGT1A8, UGT1A9, and UGT1A10 in gastrointestinal tissues is known to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor (HNF) 4α, and mediates synergistic activation by these factors. We also show that HNF4α and CDX2 are required for the expression of these UGT genes in colon cancer cell lines, and show robust correlation of UGT expression with CDX2 and HNF4α levels in normal human colon. Finally, we show that these factors are involved in the differential expression pattern of UGT1A8 and UGT1A10, which are intestinal specific, and that of UGT1A9, which is expressed in both intestine and liver. These studies lead to a model for the developmental patterning of UGT1A8, UGT1A9, and UGT1A10 in hepatic and/or extrahepatic tissues involving discrete regulatory modules that may function (independently and cooperatively) in a context-dependent manner.

Can we afford not to screen and treat hepatitis C virus infection in Canada?

Background: Screening for hepatitis C virus (HCV) followed by direct-acting antiviral (DAA) treatment in individuals born between 1945 and 1964 has been shown to be both effective and cost-effective, but the question of affordability remains unresolved. We looked at long-term cost and health outcomes of HCV screening for Ontario up to 2030. Methods: We used a validated state-transition model to analyze the budget and health impact of HCV screening followed by DAA treatment in individuals born between 1945 and 1964 versus current practice. We used a payer's perspective, discounting costs at an annual rate of 1.5%. Costs, liver-related deaths, and hepatocellular carcinoma (HCC) and decompensated cirrhosis (DC) cases detected were measured over a 14-year period. Results: By 2030, the cost of implementing a HCV screening program for individuals born between 1945 and 1964 will add an additional $845 million to the Ontario health care budget. Sensitivity analyses showed that DAA costs had the largest effect on the budget, and decreasing DAA costs to $16,000 will lead to a significantly lower budget impact of $331 million. Regarding population health, a screen-and-treat strategy will prevent 1,199 cases of HCC, 1,565 cases of DC, and 1,665 liver-related deaths by 2030. Conclusions: Contrasting the budget impact of this HCV screening strategy with other recommended health services and technologies, we conclude that HCV screening should be considered affordable. If Canada is committed to meeting the targets set out by the World Health Organization, then provinces cannot afford to not expand current screening programs.