Abstract
Elucidating the temporal natural history of Hepatitis B virus (HBV) infection provides not only useful information for assessing the spread of HBV infection but also a bedrock for economic appraisal of population-based preventive strategies (such as universal vaccination). HBV transmissions are transmitted through the maternal (vertical) route and environmental (horizontal) route. As the infection process from susceptible to active virus replication and finally to recovery state or to carrier state through both routes is not directly observable, mathematical models were therefore proposed to quantitatively elucidate the dynamic process of HBV infection with time. We began with a simple two-state model (from susceptible to infection) and further developed a five-state (including susceptible, latent phase, active viral replication, carrier, and recovery states) stochastic process to quantify the dynamics of HBV infection, making allowances for a mixed proportion of vertical and horizontal transmissions. The data used in the estimation, which were collected before implementation of a policy for universal HBV vaccination, were derived from several previous serum prevalence studies, including both low (northern) and high (southern) HBV prevalence areas, in Taiwan. The parameters obtained from stochastic models were converted to compute the basic reproductive number (R0) in each study to indicate the extent of the spread of HBV infection. By linking the temporal natural history of HBV infection with the previously established Markov process for the sequelae of HBV infection (chronic hepatitis infection, liver cirrhosis, and hepatocelluar carcinoma), we developed a Markov cycle decision tree to evaluate the two population-based preventive strategies related to vaccination and maternal lamivudine use with a cost-effectiveness analysis. In the five-state model, horizontal transmission was found to contribute more to HBV infection than vertical transmission in the northern area (59 vs. 41 %), whereas vertical transmission was more likely than horizontal transmission in the southern area (80 vs. 20 %). After considering the parameters of the two transmission routes, annual infection rate (person-years) for susceptible subjects was higher in the northern area (0.35) than the southern area (0.011). A similar finding was noted for annual rate of the transition from the latent period to active viral replications (1.12 in the northern area and 0.072 in the southern area). Annual rate of the conversion from active viral replication to the carrier state was higher in the southern area (0.184) than the northern area (0.119). Annual recovery rates were 0.014 in the northern area and 0.024 in the southern area for the carrier and 0.048 and 0.088 for transient viremia. The R0 at age 30 using the parameters obtained from the five-state stochastic model was estimated as 4.88 in the northern and 7.03 in the southern area. Regarding the findings of economic appraisal, both preventive strategies were cost-saving, yielding the negative value of incremental cost-effectiveness ratio, compared with the baseline group (no intervention), regardless of areas. The preventive strategies in the southern area were more cost-saving than those in the northern area. The consolidation of elucidating the temporal natural history of HBV infection, estimating basic reproductive number, and conducting an economic appraisal of population-based preventive strategy can aid health policy-makers in designing effective preventive strategies in other countries worldwide where HBV is still prevalent. However, the empirical findings on transmission routes and the temporal evolution of HBV infection varying with areas should be considered with great caution as only two studies were modeled.
Highlights
The temporal natural history of hepatitis B virus (HBV) infection and its sequale are long and heterogeneous (Chu 2000; Liaw and Chu 2009)
By linking the temporal natural history of HBV infection with the previously established Markov process for the sequelae of HBV infection, we developed a Markov cycle decision tree to evaluate the two populationbased preventive strategies related to vaccination and maternal lamivudine use with a cost-effectiveness analysis
The first part is to build a five-state stochastic process for modeling the temporal natural history of HBV infection characterized by the unobserved infectious process between intermediate state transitions and long-term disease progression of the sequale of HBV infection taking both vertical and horizontal transmission into account in the two areas in Taiwan
Summary
The temporal natural history of hepatitis B virus (HBV) infection and its sequale (such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma) are long and heterogeneous (Chu 2000; Liaw and Chu 2009). In the wake of acute infection, one can either recover or become a chronic carrier detected by the presence of HBsAg (the surface antigen of HBV) for more than 6 months This dynamic process of HBV infection for an individual from being susceptible until recovery or becoming a carrier is diagrammed in the upper panel of Fig. 1. In addition to the individual temporal natural history of HBV infection, the dynamic process of such HBV infection can be characterized from the population viewpoint by contact rate, transmission probability, and recovery rate, which are three measures that give the estimated basic reproductive number (R0), an indicator of the number of secondary cases produced by a primary case in traditional infectious disease models, including the widely used susceptible-infectiousrecovered (SIR) model (Anderson et al 1992). The application of the SIR or related models to a chronic infectious disease such as hepatitis B virus (HBV) infection and HCC and its related diseases is often subject to whether the temporal natural history of the infection process is well understood and whether the data are directly observed during the infectious process
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