[Cost-effectiveness of community-based treatment of chronic hepatitis B in China].

Objective: Since eliminating hepatitis B in China would need considerable public health resources, the economics problem of the strategy of community-based antiviral treatment for chronic hepatitis B (CHB) has become an important issue. The cost-effectiveness and affordability of the strategy were evaluated in this study. Methods: According to the advocacy on eliminating hepatitis B by WHO and the comprehensive protocol of community based prevention of major infectious diseases and the guideline for CHB prevention and treatment in China, the decision analytic Markov model was constructed with the parameters from national surveys or Meta-analysis. A cohort population aged 20-59 years was used as study subjects. The strategy of CHB antiviral treatment was compared with the strategies of hepatitis B vaccination and non-intervention, respectively. The costs and disability-adjusted life years (QALYs) of the strategies were calculated from the societal and payer perspectives. The incremental cost-effectiveness ratio (ICER) and the cost-effectiveness ratio (CER) were calculated for the comparison of the strategies. One-way and probability sensitivity analysis were performed for uncertainty of the results. And the cost-effectiveness and affordability curves were introduced to estimate the budget impact on the strategies. Results: In the Chinese aged 20-59 years, the ICER of CHB antiviral treatment was 37 598.6 yuan (RMB) per QALYs and the ICERs were smaller in the low age groups, indicating that the antiviral treatment strategy is cost-effective and low age groups should be the priority population. The ICER of hepatitis B vaccination was -64 000.0 yuan (RMB) per QALYs, indicating that hepatitis B vaccination is cost saving. The CER of CHB antiviral treatment ranged from 731.8 to 1 813.3 yuan (RMB) per QALYs compared with hepatitis B vaccination, and the CER of CHB antiviral treatment was higher than that of hepatitis B vaccination in all age groups, indicating that hepatitis B vaccination would be more cost-effective than CHB antiviral treatment. The price of antiviral drug, entercavir, can influence the cost effectiveness of CHB antiviral treatment. If the price of entercavir declined half, CHB antiviral treatment would be cost-saving. The probability sensitivity analysis showed that people's willing to pay for CHB antiviral treatment should not be ignored, although the results of economics evaluation of CHB antiviral treatment were reliable. The results of affordability analysis indicated that the antiviral treatment strategy could not be implemented with the budget lower than 30 million yuan (RMB), the probability of implementing the strategy was 42.6% if the budget reaches 127 million yuan (RMB), and only when the budget reaches 269 million yuan (RMB), the goal of CHB antiviral treatment strategy can be fully realized. Conclusions: Although the strategy of CHB antiviral treatment as prevention in Chinese aged 20-59 years is cost-effective, it is not an appropriate public health measure due to the high cost. The cost effectiveness would be higher by conducting hepatitis B vaccination and then antiviral treatment in susceptible population.

Cost-effectiveness analysis of antiviral therapies for hepatitis B e antigen-positive chronic hepatitis B patients in China.

BACKGROUND AND OBJECTIVE: Several antiviral therapies are now available for patients with chronic hepatitis B (CHB), but the most cost-effective strategy for Chinese patients is unclear. The aim of this study was to estimate the long-term cost effectiveness of the antiviral treatments (lamivudine, adefovir, telbivudine and entecavir) for hepatitis B e antigen (HBeAg)-positive CHB patients in China. METHODS: A Markov model was used to simulate the life-time (41-year time span) costs and effectiveness associated with antiviral treatments from the perspective of Chinese healthcare. Relative model parameters were derived from Chinese population studies. Costs and effectiveness were discounted at 5 %. The highest retail prices for generic and branded drug prices were also considered. Probabilistic sensitivity analysis and one-way sensitivity analysis were used to explore model uncertainties. RESULTS: In the base-case analysis, the least quality-adjusted life years (QALYs) were obtained with adefovir as the reference strategy. Lamivudine generated the highest incremental cost-effectiveness ratio (ICER), with an additional US$35,000 needed to gain one additional QALY for generic drugs and US$36,000 for branded drugs. Entecavir had the lowest ICER of US$7,600 and US$9,100, respectively. The projected 10-year cumulative incidences of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC) and mortality for entecavir were lower than the other strategies. In probabilistic sensitivity analyses, entecavir was the preferred option at a threshold of US$18,924 per QALY. CONCLUSIONS: In patients with HBeAg-positive CHB in China, entecavir is a cost-effective option compared with other therapies for CHB.

Assessment of differences in the conformational flexibility of hepatitis B virus core-antigen and e-antigen by hydrogen deuterium exchange-mass spectrometry.

Hepatitis B virus core-antigen (capsid protein) and e-antigen (an immune regulator) have almost complete sequence identity, yet the dimeric proteins (termed Cp149d and Cp(-10)149d , respectively) adopt quite distinct quaternary structures. Here we use hydrogen deuterium exchange-mass spectrometry (HDX-MS) to study their structural properties. We detect many regions that differ substantially in their HDX dynamics. Significantly, whilst all regions in Cp(-10)149d exchange by EX2-type kinetics, a number of regions in Cp149d were shown to exhibit a mixture of EX2- and EX1-type kinetics, hinting at conformational heterogeneity in these regions. Comparison of the HDX of the free Cp149d with that in assembled capsids (Cp149c ) indicated increased resistance to exchange at the C-terminus where the inter-dimer contacts occur. Furthermore, evidence of mixed exchange kinetics were not observed in Cp149c , implying a reduction in flexibility upon capsid formation. Cp(-10)149d undergoes a drastic structural change when the intermolecular disulphide bridge is reduced, adopting a Cp149d -like structure, as evidenced by the detected HDX dynamics being more consistent with Cp149d in many, albeit not all, regions. These results demonstrate the highly dynamic nature of these similar proteins. To probe the effect of these structural differences on the resulting antigenicity, we investigated binding of the antibody fragment (Fab E1) that is known to bind a conformational epitope on the four-helix bundle. Whilst Fab E1 binds to Cp149c and Cp149d , it does not bind non-reduced and reduced Cp(-10)149d , despite unhindered access to the epitope. These results imply a remarkable sensitivity of this epitope to its structural context.

Quantitative assessment of the antiviral potencies of 21 shRNA vectors targeting conserved, including structured, hepatitis B virus sites.

BACKGROUND & AIMS: RNA interference (RNAi) may offer new treatment options for chronic hepatitis B. Replicating via an RNA intermediate, hepatitis B virus (HBV) is known to be principally vulnerable to RNAi. However, beyond delivery, the relevant issues of potential off-target effects, target site conservation in circulating HBV strains, and efficacy of RNAi itself have not systematically been addressed, nor can the different existing data be quantitatively compared. The aim of this study was to provide such information. METHODS: To focus on the intracellular RNAi process itself and minimise other variables affecting overall RNAi efficacy, we used a robust co-transfection system to quantitatively assess the relative potencies of 21 small-hairpin (sh) RNA vectors, targeting conserved sites throughout the HBV genome, against viral RNAs, proteins, nucleocapsids, and secreted virions under standardised conditions. RESULTS: The approach enabled a distinct efficacy ranking, with the six most potent shRNAs achieving 95% reductions in virion formation, sequence-specifically and without detectable interferon induction, yet by differentially affecting different steps. Efficacy correlated poorly with predictions and was not principally abolished by target structure. Sequence comparisons suggest that truly conserved, RNAi-targetable sequences comprise less than 500 nucleotides of the circulating HBV genomes. CONCLUSIONS: The HBV genome can harbour only a finite number of optimal target sites, but current predictions are poorly suited to constrain the number of possible candidates. However, the small size of the highly conserved sequence space suggests experimental identification as a viable option.

Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis.

BACKGROUND: Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. AIM: To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. METHODS: We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). RESULTS: Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. CONCLUSION: The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.

Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B.

OBJECTIVE: To evaluate the cost effectiveness of treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with entecavir compared with lamivudine with adefovir salvage, based primarily on the results of a recent 2-year, randomised, multicentre, clinical trial (n = 709). Previous economic analyses have been limited by the lack of comparative clinical data for entecavir and lamivudine beyond 1-year duration and for salvage therapy. METHODS: We conducted a cost-utility analysis using a Markov model from a US-payer perspective over a lifetime time horizon. The hypothetical cohort was 35-year-old patients with HBeAg-positive CHB. We evaluated 2 years of treatment with entecavir 0.5mg/day versus lamivudine 100mg/day, plus addition of adefovir 10mg/day for patients who developed virologic breakthrough due to resistance to either drug. In a scenario analysis, we considered adefovir plus lamivudine combination therapy for treatment-naive patients. Clinical and economic inputs ($US, year 2006 values) were derived from publicly available data, and probabilistic sensitivity analyses were conducted to evaluate uncertainty in the results. RESULTS: The estimated 10-year cumulative incidence of cirrhosis for patients initiated on entecavir was 2.3% lower than for those on lamivudine (20.5% vs 22.8%). The discounted incremental cost per QALY gained was $US7600 in the base-case analysis, and the 95% central range from probabilistic sensitivity analysis was $US2500-$US19 100. Combination therapy for treatment-naive patients led to an increase in costs without improvement in patient outcomes compared with entecavir monotherapy. CONCLUSIONS: Our analysis suggests entecavir improves health outcomes in a cost-effective manner compared with lamivudine with adefovir salvage or combination therapy, and highlights the importance of using evidence-based effectiveness estimates in economic studies of CHB therapies.

[Construction and biological activity assessment of core mutants of hepatitis B virus adr subtype].

OBJECTIVE: To construct the core mutant (L97 and V60) plasmids of hepatitis B virus (HBV) and assess their biological activity. METHODS: Site-directed mutagenesis was performed to induce specific core point mutations in HBV adr suhtype 1.2 copy genome plasmid p3.8 II. The plasmids were transfected into HepG2 cells via liposome, and intracellular HBV DNA was analyzed by Southern hybridization, while extracellular HBV antigens (HBsAg and HBeAg) in the culture supernatant were assayed by enzyme-linked immunosorbent assay. RESULTS: Sequence analysis of the constructed mutant plasmids p3.8 L97 and p3.8 V60 demonstrated mutations at 2 189 A C and 2 086 C HBV adr subtype genome core mutant (L97 and V60) plasmids we have constructed possess biological activity.G respectively. These mutant plasmids exhibited HBV DNA replication activity and gene expression in host cells. CONCLUSION: HBV adr subtype genome core mutant (L97 and V60) plasmids we have constructed possess biological activity.

A non-invasive assessment of hepatitis B virus carrier status using saliva samples.

A non-invasive testing method to determine hepatitis B virus (HBV) carrier status in pregnant women was evaluated. Paired serum and saliva samples were collected and assessment of hepatitis B markers were performed. Of the 502 women enrolled, 5.6% (28/502) of their sera were found to be positive for HBV surface antigen (HBsAg). Assessment of 28 HBsAg seroreactive and 200 HBsAg sero-non-reactive paired saliva samples showed that 17 saliva contained HBsAg. Fourteen of the saliva reactive samples were matched to the serum reactive samples (50% sensitivity); and 3 saliva samples were positive for HBsAg among 200 subjects seronegative for HBsAg (98.5% specificity). Seven of the 28 HBsAg positive sera were found to be reactive for HBV envelope antigen (HBeAg) (25%). One of seven HBeAg seroreactive and 16 HBeAg seronegative paired saliva samples tested were non-reactive for HBeAg. This report found a non-invasive saliva testing method to be a possible alternative approach for determining chronic HBV carrier status if the sensitivity of the test can be improved.