In a country where the estimated number of HBsAg-positive cases is more than 3.2 million, the total amount of treatment eligible patients, which was quantified through population data and the large patient database constructed for this study, is 828,000, and of these, around 108,000 are patients with liver cirrhosis. If these eligible patients are not identified and treated, about 12,800 deaths are expected to occur each year due to liver related complications, leading to a cumulative number of 256,788 (31 %) in 20 years. The number of liver transplant patients in Turkey is 400–500 per year and this treatment is covered by the health insurance [50
]. If we would modestly assume that 50 % of liver transplantations are due to HBV, there will be a total of about 4,000 liver transplantations that will take place in 20 years, while the demand will be around 49,000, according to our estimates. On top of all the life years lost, and more severe treatment options such as liver transplantation are needed, the 20-year cumulative medical management cost of an untreated active HBeAg-positive and HBeAg-negative CHB (no-cirrhosis) patient will be 25,781 TL (€12,800), and 48,198 TL (€23,900), respectively.
If the estimated active CHB cohort is identified and treated with the most cost-effective drug, liver related mortality and morbidity can be reduced by almost 80 %. Comparing treatment scenarios to the no antiviral treatment scenario in all the sub-cohorts, the tenofovir strategy was the most cost-effective. The ICER for HBeAg-positive and negative CHB (non-cirrhosis), and HBeAg-positive and negative cirrhosis was 638 TL (€306), 15,573 TL (€7,800), 5,300 TL (€2,600), and 6,609 TL (€3,300), respectively. Both entecavir and tenofovir, compared to the do nothing scenario, had the same amount of health gain. A recent systematic review and Bayesian meta-analysis concludes that in the first year of treatment for CHB, tenofovir and entecavir are the most potent oral antiviral agents for HBeAg-positive patients, while for HBeAg-negative patients tenofovir is most effective [51
]. According to net sold medication counts per year in Turkey, it was calculated that no more than 10 % of active CHB patients receive antiviral treatment [52
], indicating a massive shortcoming in providing eligible patients with life prolonged and even life saving treatments. At individual level the association of disease progression with increased cost of disease management suggests that measures to prevent or delay progression of CHB related liver diseases will be economically beneficial. At population level, however, the impact of therapy on the overall number of people with chronic infection will remain limited as long as the majority of infected patients will not receive treatment due to lack of recourse for optimal treatment.
The future public health burden of chronic hepatitis B could potentially be reduced by antiviral treatment [53
]. The recommendations by the Turkish Association for the Study of the Liver (TASL) [52
] to treat eligible patients are in line with the European Association for the Study of the Liver [2
] criteria, except that liver biopsy evidence is always required to start treatment in patients with no established cirrhosis. Almost all patients are reimbursed for treatment of viral hepatitis through the national insurance system in Turkey. A new modification issued in 2009 by the department within Turkish Health Authorities responsible for reimbursement decisions, states that lamivudine should be the first line therapy in all patients with viral load lower than 107
copies/mL. This is largely due to the low costs of lamivudine and to the recent data about on-treatment monitoring approach, using serum HBV DNA level as a predictor for efficacy and drug resistance. We assessed whether this scenario (roadmap concept) was cost-effective in an HBeAg-negative non-cirrhotic patients group, since sufficient data were available for this sub-group. The ICERs of both scenarios, roadmap concept [15,829 TL (€7,875)] and tenofovir monotherapy [15,573 TL (€7,747)], were equal. Although eight healthy life years were gained by tenofovir monotherapy while this was only three healthy life years gained for the roadmap concept scenario.
According to our outcomes, the roadmap concept could be an alternative strategy to consider for a country with a large HBeAg-negative disease, where tenofovir is not available. This scenario could also be suggested in resource poor settings, since the cumulative costs to treat are less compared to tenofovir monotherapy. Various studies have examined the cost-effectiveness of antiviral therapy for CHB and have concluded that treatment is cost-effective versus no treatment [10
]. Kanwal et al. [10
] found that lamivudine monotherapy strategy was more expensive and less effective than treatment with interferon or salvaged by adefovir. According to our analysis, lamivudine monotherapy was less effective as well, but was not more expensive compared to other treatment strategies. This can be explained by the fact that more than 5 years have elapsed between both studies during which the price of lamivudine has decreased. Buti et al. [57
] concludes that first-line treatment with tenofovir is cost-effective for both HBeAg-positive and negative patients, in comparison to other antivirals. They also conclude that tenofovir was more effective than entecavir, which is in contrast to our results for which the efficacy equality was equal for both drugs.
A country with similar patient characteristics and health care system may benefit from our scenario analysis and outcomes related to the burden of disease. Considering the economic affordability in different countries, the cost-effectiveness thresholds may be different. It may be that in a country where the threshold is high, a more expensive but effective drug is cost-effective, while this might not be the case for this same drug in a country with a lower cost-effectiveness threshold. A review study by Barbieri et al. [58
] on the generalizability of cost-effectiveness studies concludes that the differences in cost-effectiveness results between countries are not systematic, which makes inferences from one country to another difficult.
A limitation of our study is that we used simplified assumptions (e.g., we did not consider coinfection with other viruses or toxins such as alcohol that will accelerate progression), and we assumed the cohort to be static, so there were no new cases added to the cohort. Also, the assumption that the development of resistance both with entecavir and tenofovir for the coming 20 years will stay at 0–1 % per year may underestimate what will happen as longer term data are collected. We took a rather conservative approach by only including high HBV DNA and ALT >2 × ULN. If, like in the guidelines, we had taken elevated ALT levels but starting at 1 × ULN, the number of eligible patients would have increased. Another factor that surely plays an important role in the estimation of eligible patients is the inclusion of data from tertiary centres. In Turkey, data on viral hepatitis are collected at the provincial health directorate, but only for acute (incident) cases. Thus, the data on CHB patients is derived from clinical settings, of which not all patients coming to the hospital have active disease. Some patients are detected during the diagnostic process for other diseases and referred to the hepatology department. We conclude that the cohort data from Turkey are, therefore, likely to be biased towards more active CHB cases, which could mean that the number of eligible patients might be an overestimation. One way to account for this bias would be to implement new information systems and registries to facilitate the notification, counseling, and medical management of persons with CHB infections in countries with intermediate or high endemicity. Any attempt to predict the future is likely to be biased. Therefore, our projections and estimates regarding future treatment rates and liver-related deaths are only intended to provide a crude overview of the public health impact of antiviral therapy.
Identification of chronic hepatitis B infected individuals is essential to ensure that infected persons receive necessary care to prevent or delay onset of significant liver disease and services to prevent transmission to others. Achieving identification could be done by monitoring inactive cases annually, as is recommended in the guidelines. Antenatal screening should be routinely performs, and new information systems and registries should be implemented to facilitate the notification, counselling, and medical management of persons with chronic HBV infection in countries with intermediate and high endemicity. Given the substantial mortality and morbidity attributable to HBV related chronic liver diseases, the control of progression to cirrhosis, decompensated cirrhosis and liver cancer will continue to be an important public health priority. Third generation drugs, such as entecavir and tenofovir, with high effectiveness and low resistance profiles, should be made more affordable to help people with active chronic hepatitis B lead healthier lives.