http://orcid.org/0000-0003-1582-3379
Figures
Abstract
Background
Hepatitis D virus (HDV), which requires the presence of hepatitis B virus (HBV), is a deadly yet neglected disease that rapidly leads to liver cancer and disease-induced mortality. This co-dependence creates complex transmission dynamics that make it difficult to predict the efficacy of interventions aimed at HBV and/or HDV control in endemic regions, such as certain municipalities of Brazil, where up to 65% of HBV-infected persons are co-infected.
Methodology
We created a mathematical model that captures the joint transmission dynamics of HBV and HDV, incorporating mother-to-child, sexual and household transmission. With an aim to minimize the number of total infections and disease-induced mortality in 2027, we then determined optimal strategies for Brazil and its sub-regions under a constrained budget, which was dynamically allocated among HBV and HDV screening, HBV and HDV treatment, HBV newborn and adult vaccination, and awareness programs. Three treatment options were considered, namely: Tenofovir, PEGylated-Interferon, and nucleic acid polymers (NAP).
Results
The additional cost of HDV screening and the use of a more expensive PEGylated-Interferon are offset by not wasting resources on treating co-infected persons with Tenofovir. The introductory price of NAP treatment must be less than $16,000 per course to become competitive with Tenofovir and PEGylated-Interferon in Brazil.
Conclusion
Additional screening for HDV is beneficial, even in a low HBV and HDV endemic regions of Brazil. We recommend PEGylated-Interferon, wherever possible, for both HBV and HDV. If PEGylated-Interferon is not available in abundance, PEGylated-Interferon for co-infections and 4-year Tenofovir treatment for mono-infections is recommended.
Citation: Goyal A, Romero-Severson EO (2018) Screening for hepatitis D and PEG-Interferon over Tenofovir enhance general hepatitis control efforts in Brazil. PLoS ONE 13(9): e0203831. https://doi.org/10.1371/journal.pone.0203831
Editor: Isabelle Chemin, Centre de Recherche en Cancerologie de Lyon, FRANCE
Received: March 26, 2018; Accepted: August 28, 2018; Published: September 7, 2018
Copyright: © 2018 Goyal, Romero-Severson. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by National Institutes of Health (grant numbers R01-AI116868, R01-AI028433, R01-OD011095 and R01-AI087520). Portions of this work were performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Together, hepatitis B virus (HBV) and hepatitis D virus (HDV) are a major global health burden with approximately 240 million infections worldwide [1]. Although HBV itself is a major chronic illness that leads to liver cirrhosis, hepatocellular carcinoma, and death, co-infection with HDV increases disease progression rates by 5–10 fold. Therefore, the presence of HDV significantly amplifies the morbidity and mortality of existing HBV epidemics and negatively affects the performance of interventions aimed towards HBV eradication [2–4].
The majority of chronic HBV carries reside in developing or under-developed regions such as Asia Pacific and sub-Saharan Africa, where chronic HBV infection is highly endemic (>8% prevalence). Intermediate HBV endemic regions have 2–7% chronic HBV prevalence and include regions such as North Africa and the Middle East, parts of Eastern and Southern Europe, parts of Latin America, and South Asia. More developed regions/countries such as Australia, Asia, Northern and Western Europe, Japan, North America, and some countries in South America represent low endemic regions, where chronic HBV is prevalent in less than 2% of the population [5]. Unlike HBV, there is no clear classification of HDV prevalence due to lack of our knowledge of HDV epidemiology in different regions of the world [6]. As a matter of convention, we define low, moderate, and high-endemic HDV infection as ≥8%, 2–7% and <2% HDV prevalence in HBV infected population, respectively.
In 2017 Brazil had approximately 1.5 million HBV carriers [7], of which about 8% were co-infected with HDV [8]. The distribution of HDV co-infection is spatially heterogeneous, reaching as high as 65% in some parts of Brazil such as the Amazon Basin [9–11]. Brazil constitute of regions that range from both high to low-endemic HBV and high to low-endemic HDV. Effective intervention to reduce HDV prevalence is complicated by the fact that there is no direct vaccination or effective treatment for HDV [12–14]. However, HDV can only infect person already infected with HBV, raising the possibility of indirect prevention methods by treating either HBV-only or co-infected persons [15]. Despite being deadly and widespread in some populations, HDV infections are largely neglected as a public health intervention target [14].
In 2002 [16] the Brazilian government implanted a newborn HBV vaccination program that reached over 90% by 2015 [17]. However, coverage is heterogeneous remaining on the lower side (69–87%) in the Amazon Basin [18]. Extremely high HDV prevalence is currently limited to the Amazon Basin, but it still poses a huge health risk to the rest of the country and broader region as a consequence of an increased migration to and from the Amazon Basin [19]. Over the past decade, the Brazilian government has also incorporated free HBV testing in HIV centers and universal access to hepatitis treatment in its public health agenda [20]. However given limited public health budgets, these additional measures are unlikely to have a large effect on HBV and HDV prevalence [20]. The economic burden of universal treatment for all diagnosed HBV (and HDV) infections would be substantial, especially if unaware HBV and HDV carriers continuously produce new infections. In this case, it becomes important to, (i) diagnose unaware HBV infections [21], (ii) diagnose unaware HDV infections, (iii) treat diagnosed HBV infections [21], (iv) treat diagnosed HDV infections, (v) increase newborn vaccination coverage, and (vi) spread awareness in the population to prevent the incidence of new infections. However, given limited public health resources, it is impossible to apply all these interventions at the same time. Optimal triage of limited public health resources in Brazil is essential for limiting the spread of HDV.
We implemented a mathematical model of joint HBV and HDV epidemics in Brazil accounting for age structure, mother-to-child transmission, household transmission and horizontal transmission to study the efficacy of alternative investment strategies. Mathematical modelling assists public health policy-makers in making informative decisions [22–24] and formal models are especially important in complex, multi-pathogen systems such as HBV and HDV [2–4], where intuitive reasoning may be insufficient. The model we use in this analysis is an extension of previously published work on HDV in China [25]. Unlike China, Brazil is a low HBV endemic region with sub-regions of moderate and high HBV and HDV prevalence but the control of HDV in Brazil is still more difficult due to increased burden of disease and reduced public health resources [16, 25]. We find the dynamic allocation of resources year-to-year between different controls (screening, vaccination, treatment, and awareness) under different treatment policies that reduce new cases of HBV and mortality from 2017–2027.
Material and methods
Model structure
The model is represented by a system of 22 ordinary differential equations (see section A in S1 File). The population consists of two different age groups, (i) child (age≤14 years), and (ii) adult/sexually-active (age>14 years). These two age groups were categorized into four main compartments, (i) susceptible individuals; (ii) HBV mono-infected individuals, (iii) HBV-HDV co-infected individuals, and (iv) recovered individuals who are immune to future mono- and co-infections. Both mono- and co-infected women transmit HBV infection perinatally but not HDV [26]. If vaccinated at birth, newborns acquire immunity against HBV and HDV. Mono- and co-infected adults also contribute to new HBV and HDV infections in the adult population through horizontal (i.e. sexual) transmission. Furthermore, susceptible children can also acquire HBV and HDV infections through (non-sexual) interactions with infected persons (both adults and children) though household transmission [27]. The model structure is illustrated in Fig 1.
Green, orange, pink and blue boxes represent recovered, susceptible, HBV mono-infected, and HBV-HDV co-infected groups in the population. Text in red represent one of the five interventions applied: (i) HBV newborn vaccination (ii) HBV diagnosis and adult vaccination, (iii) antiviral treatment for HBV infected individuals, (iv) antiviral treatment for HBV and HDV infected individuals, and (v) awareness programs.
Model calibration
We identified population parameters (Table A in S1 File) and treatment costs (Table 1) from the literature. The prevalence of HBV and HDV in both age groups (Table 2 and section D in S1 File) at the beginning of each simulation were also identified from surveys conducted in Brazil.
Intervention model
Our model is inclusive of following five interventions (also illustrated in Fig 1),
- Implementation of HBV and/or HDV infection screening/diagnosis and HBV adult vaccination,
- Implementation of antiviral treatment for mono-infected individuals,
- Implementation of antiviral treatment for co-infected individuals,
- Implementation of awareness programs,
- Increase in newborn vaccination coverage from the baseline coverage of 95% and 80% coverage in Brazil and the Amazon Basin, respectively [18, 36].
The diagnosis process has two phases. In the first phase, a person is tested for HBV and, if positive for HBV, then tested for HDV. If they are positive on both tests, then they are immediately considered a candidate for antiviral treatment. However, if the person comes out as HBV positive but HDV negative, then the medical recommendation is to re-test in 6 months to determine true HBV status [2]. In the second phase, persons with a previous positive HBV test are re-tested for both infections. If the HBV test or both come out positive, then a person is immediately considered a candidate for antiviral treatment as a mono- or co-infected individual respectively. In either phase of testing, if an adult is determined to be both uninfected and unvaccinated, we assume they are given HBV adult vaccination to induce future immunity to both infections and are not tested further. HBV positivity is confirmed by the presence of either HBsAg or HBV DNA while an individual is additionally confirmed positive for HDV through HDV RNA [25]. In the model, we further assumed that 5%(1–10%) of the adult population can be diagnosed every year, based on the assumption that each of the >7000 hospital can test 1–10 person every day [52].
Diagnosed infections, as they become aware of their infection status, if not receiving treatment are assumed to transmit infections at a lower rate compared to undiagnosed infections [25]. On the other hand, diagnosed infections under treatment are assumed to be not transmitting for the treatment duration because of behavioral changes and huge suppression in HBV DNA levels in individuals resulting from treatment [15]. Furthermore, infected individuals who fail treatment are assumed to transmit infections at the same rate as diagnosed infections without treatment. The awareness programs promoting safer sex and use of condoms are assumed to induce behavioral changes in the population leading to a reduction in the horizontal transmission rate of both HBV and HDV.
We employed two best treatment options currently available for mono-infected and co-infected individuals, PEGylated-Interferon (PEG-IFN) and Tenofovir (TDF). The 48 weeks of PEG-IFN treatment costs approximately 9 times than one-year treatment with TDF; however the efficacy of the PEG-IFN treatment for mono-infected is approximately three times than of TDF. Moreover, the efficacy of TDF for co-infected individuals is zero while PEG-IFN for co-infected is as effective as for mono-infected individuals. The efficacy and costs of all interventions are given in Table 1.
Furthermore, the feasibility of the implementation of an upcoming promising therapy (i.e. 1-year of nucleic acid polymer therapy or NAP) [53, 54] for both mono-infections and co-infections in Brazilian public health system (at the national level) is also tested in a crude manner by assuming different introductory prices. The expected sustained virological response (SVR) efficacy of NAP is 80% for mono-infections and 42% for co-infections [53].
We propose five strategies based on different combinations of five interventions as following,
- Strategy-1: None of the five interventions.
- Strategy-2: All five interventions but with no testing for HDV and thus, assuming all infections are mono-infections and the choice of treatment here is 1-year TDF.
- Strategy-3: All five interventions with testing for HDV and the choice of treatment here is 1-year TDF and 1-year PEG-IFN for mono-infections and co-infections, respectively.
- Strategy-4: All five interventions with testing for HDV and the choice of treatment here is 4-year TDF and 1-year PEG-IFN for mono-infections and co-infections, respectively.
- Strategy-5: All five interventions with testing for HDV and the choice of treatment here is 1-year PEG-IFN for all infections.
Optimal controls
The objective is to simultaneously reduce the number of HBV and HDV infections residing in the population as well as the disease-induced deaths. We employed Genetic Algorithm [55] in MATLAB R2016b to determine the optimal level of the implementation of interventions for a given year under any strategy for a constrained yearly budget (the derivation of costs is given in the section B in S1 File [25]) that is assumed to increase at 11% yearly while the cost of all interventions are discounted at 3% yearly (see section C in S1 File). We also considered an unlimited resources situation to determine the maximum improvement in controlling HBV and HDV epidemics that one can observe on different levels in Brazil, (i) national level (Brazil), (ii) state level (State of Acre), (iii) city level (Manaus and Eirunepé city), and (iv) municipality level (Lábrea Municipality). The prevalence information in all these regions is given in Table 2.
Results
Intervention effectiveness with unlimited treatment resources
The effect of interventions on the prevalence of hepatitis is first determined under the assumption that the only limiting factor is the public health infrastructure available to screen people (Fig 2). That is, all infected individuals that are diagnosed through screening are treated, regardless of the cost. This also establishes an upper limit for intervention efficacy for a given level of screening capacity.
The maximum screening rate (ρ0) and HDV prevalence in HBV mono-infected individuals are varied across columns and rows, respectively while the prevalence of HBV in the population is varied on the x-axis of each subfigure. The screening rate can be interpreted as approximately the proportion of the population that can be screened each year. The black dashed line shows the reduction in hepatitis prevalence (both mono- and co-infections) from treating HBV-only with a 4-year course of TDF and co-infections with 1-year PEG-IFN, while the red line shows the effect of treating everyone with PEG-IFN.
When treatment resources are unconstrained, the major determinant of the effect of interventions is the screening rate. Likewise, treating everyone with PEG-IFN is always better regardless of the joint prevalence or the screening rate. This is evident by the fact that the red line representing prevalence with universal PEG-IFN treatment is below the dashed black line prevalence under universal TDF treatment for all plots in Fig 2. In all settings, the effectiveness of interventions implemented also increases as the prevalence of HDV increases. When treatment resources are unconstrained, all co-infected individuals are being treated with PEG-IFN rather than TDF, the latter being ineffective for co-infected individuals. This increased effectiveness comes at a very high cost, as unlimited treatment in high-prevalence settings requires substantial ongoing investment that far surpasses most public health budgets (Figure A in S1 File). However, by assuming that an infection prevented/cured saves at least 10 life years with a quality of life measure of 0.75 [25], we still find that it is cost-effective to explicitly conduct HDV testing and treat HDV infections with PEG-IFN (as the cost per quality-adjusted-life-years (QALYs) saved is always smaller than the 3×GDP ($25,947) of Brazil [56]) (Figure B in S1 File).
Intervention effectiveness with realistic budgets
Public health budgets for hepatitis prevention in Brazil are small (less than $1 USD per person-year, see Table 2). In this section, we consider how to optimally allocate resources within 5 intervention strategies at multiple scales in Brazil, which were found to be dynamic on a year to year basis (shown for Brazil under strategy 4 in Fig 3). We attempt to answer 2 questions: 1) does screening for co-infection improve intervention effectiveness, and 2) if so, what is the best treatment strategy for a screening program that tests for both HBV and HDV?
We consider 5 basic scenarios: 1) no intervention to establish a baseline, 2) untargeted intervention that screens for HBV-only (i.e. does not identify co-infection), 3) targeted intervention that treats HBV-only with 1-year TDF, 4) targeted intervention that treats HBV-only with 4-year TDF, 5) targeted intervention that treats HBV-only with 1-year PEG-IFN. In the targeted interventions, all co-infected persons are treated with 1-year PEG-IFN. We also analyze 5 different regions with variable levels of HBV and HDV prevalence: Brazil (Table 3); Manaus, a city in Amazonas state, (Table 4); Lábrea, a municipal region in Amazonas state, (Table 5); Eirunepé, a different city in Amazonas state (Table 6); and, Acre State, a state in Brazil (Table 7).
Comparing the no-intervention strategy (baseline) to any other intervention strategy, we see that intervention effects are modest, which is expected given the low-efficacy of treatment and limited treatment resources. However, we also see that even with these highly limited budgets, it is possible to see at least 189,300 fewer cases under strategy 5 at the national level compared to the baseline (calculated as HBP under strategy 5 minus HBP under strategy 1 in Table 3).
To address the first posed question, we compared strategy 2 to strategies 3, 4, and 5. Strategy 2 (the untargeted strategy) was never the best option. This result makes it clear that the additional cost of screening and the use of a more expensive PEG-IFN are offset by not wasting resources on treating co-infected persons with TDF. The difference between strategy 2 and strategies 3, 4, and 5 are the least pronounced at the national level (Table 3). This is because the national prevalence of HBV is much lower (~0.6%) than in specific sub-regions. Areas with high prevalence of co-infection will generally benefit less from targeted screening; however, even in low HBV and moderate HDV endemic region, we see that some of the targeted screenings outperform the untargeted strategy.
In all sub-national regions, we see that strategy 5 is always the best in terms of reducing the joint prevalence of HBV and HDV along with hepatitis caused mortality. However, the differences between treating HBV mono-infected individuals with either 4 years of TDF or PEG-IFN were very small suggesting that either strategy may be effective in smaller regions. Generally, in high HDV prevalence regions of Brazil, we can say that the increased cost of treating everyone with PEG-IFN is offset by better public health outcomes even with small budgets. Likewise, if PEG-IFN is not available, it is better to treat with 4 years of TDF than 1 year. However, the efficacy of treating everyone with PEG-IFN declines when the prevalence of HDV is low.
We also performed a conservative cost-effectiveness analysis at the national level by assuming that an infection prevented/cured saves at least 10 life years with a quality of life measure of 0.75 [25]. In general, all of the hypothetical interventions are cost-effective; yet different interventions have different population-level effects even when budgets are small. With the most number of infections prevented/cured, the strategy 4 would save at least 1.42×106 quality-adjusted-life-years (QALYs) (calculated as the assumed number of number of quality life years saved per prevented case (10 years * 0.75 = 7.5 years) times the number of prevented cases (HBP under strategy 4 minus HBP under strategy 1 in Table 3)) but at an additional cost of $511 million compared to the baseline, which yields cost per QALY as $388, which is significantly higher than the 3×GDP ($25,947) of Brazil [56].
Furthermore, a doubling of the budget leads to an additional 27,600 infections being prevented/recovered at the national level while at the regional level, the impact of budget doubling was either modest or insignificant (Table 8).
Will the implementation of upcoming NAP therapy be better than existing options and at what introductory price?
One upcoming promising therapy for both mono-infections and coinfections is NAP [53, 54], which might be available soon. With an expected introductory price of ~$50,000 (assuming similar to PEG-IFN, when it was first introduced), we found that despite high efficacy of NAP treatment, its inclusion will have less impact in reducing the joint prevalence of two viruses than the existing best treatment option in Brazil (4-year TDF for mono-infections and 1-year Peg-IFN for co-infections) (Fig 4). The introductory price of NAP treatment must be less than $16,000 per person to become competitive with existing therapies.
The x-axis gives the cost per course of NAP treatment and the y-axis show the number of additional cases caused by using universal NAP therapy instead of alternative 1-year PEG-IFN for co-infections and 4-year TDF for mono-infections (negative values indicated prevented cases). Universal NAP therapy compared to PEG-IFN for co-infections and TDF for mono-infections are approximately equal at a cost of about $16,000 for a single course of NAP.
Discussion
In Brazil, mono-infections and co-infections are generally isolated to regions with the lowest access to health services and lowest prevention budgets. Moreover, the natural barriers that keep HDV contained in certain regions of Brazil are breaking down with increasing industrialization and access to remote areas. Given the high levels of HBV infection in Brazil and the surrounding countries, control and containment of HDV is essential and increasingly important for the broader population health of the entire region and potentially the entire world. Although, the Brazilian government created the National Viral Hepatitis Program in 2012, optimization of the available resources to contain/eradicate HBV and HDV epidemics is missing.
This model suggests that, given realistic budgets and heterogeneous levels of both HBV and HDV infection in various regions of Brazil, screening for HDV provides additional population-level benefits that offset the additional costs. Moreover, WHO does not recommend PEG-IFN or IFN but only Entecavir/Tenofovir due to cost issues in developing regions with limited resources [30], while also not factoring HDV in their analysis. However, our analysis supports that PEG-IFN, though more expensive, generally produces greater reductions in the incidence and prevalence of HBV in the general population, in consistent with [57]. Our analysis also agrees with the suggested implementation of free HBV and HDV screening followed by an adequate treatment and vaccination strategy in China, another resource-constrained environment [58]. Our model also allowed us to make an estimate of the cost per QALY saved ($388) for the best treatment strategy (4 year TDF for mono-infections and 1 year PEG-IFN for co-infections), which was in line with previous estimates for universal TDF treatment [41]. Despite low efficacy, a substantial investment was also made to awareness programs as they played an important role in the optimal control of HDV and HBV in Brazil [59].
Moreover, one of the significant barriers to HBV (and HDV) control is the lack of effective and inexpensive therapies. New therapies such as NAP that may become available soon have shown promising results in clinical trials [53, 54], but the expected high cost of new pharmaceuticals may render the treatment useless on a population level. We expect that only when the introductory price of NAP would be less than $16,000, it would be beneficial for the Brazilian government to include it in public health system over currently available therapeutic options.
Despite the usefulness of our model, it can be further improved. For example, future models can reflect that TDF receiving mothers have a very low probability of vertical transmission [60]. Furthermore, one can also incorporate the treatment for HBV-infected children [61, 62], with SVR of 10% under 24 weeks IFN therapy and SVR of 2% under 72 weeks of TDF treatment [63]. Unfortunately, there are no pediatric recommendations to treat HDV currently [64]. The fact that we do not know the additional amount spent at the state level by state governments on hepatitis viruses means that our state-level budgets are likely underestimates [45]. However, our results suggest that small changes to the total budget will not change the inference qualitatively and the quantitative effect will be a small underestimation of the number of preventable cases.
In conclusion, we support an additional screening for HDV even in a low HBV and HDV endemic region. Moreover, we recommend PEG-IFN, wherever possible, for all infections. However, if PEG-IFN is not available in abundance, PEG-IFN for co-infections and 4-year TDF treatment for mono-infections is highly desirable to achieve HBV and HDV control, even in countries where the per capita health budget is less than $1.
Supporting information
S1 File. Supplementary material and methods.
Detailed explanation and formulation of the mathematical model, cost functions, parameter values used in the model.
https://doi.org/10.1371/journal.pone.0203831.s001
(DOCX)
Acknowledgments
This work was supported by National Institutes of Health (grant numbers R01-AI116868, R01-AI028433, R01-OD011095 and R01-AI087520). Portions of this work were performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
References
- 1. Wranke A, Pinheiro Borzacov LM, Parana R, Lobato C, Hamid S, Ceausu E, et al. Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN). Liver international: official journal of the International Association for the Study of the Liver. 2018;38(5):842–50. Epub 2017/10/01. pmid:28963781.
- 2. Goyal A, Murray JM. Recognizing the impact of endemic hepatitis D virus on hepatitis B virus eradication. Theor Popul Biol. 2016;112:60–9. pmid:27594346.
- 3. Xiridou M, Borkent-Raven B, Hulshof J, Wallinga J. How hepatitis D virus can hinder the control of hepatitis B virus. PLoS One. 2009;4(4):e5247. Epub 2009/04/22. pmid:19381302; PubMed Central PMCID: PMCPMC2668760.
- 4. Goyal A, Murray JM. The impact of vaccination and antiviral therapy on hepatitis B and hepatitis D epidemiology. PLoS One. 2014;9(10):e110143. pmid:25313681; PubMed Central PMCID: PMCPMC4196970.
- 5. MacLachlan JH, Cowie BC. Hepatitis B virus epidemiology. Cold Spring Harbor perspectives in medicine. 2015;5(5):a021410. Epub 2015/05/03. pmid:25934461; PubMed Central PMCID: PMCPMC4448582.
- 6. Rizzetto M. Hepatitis D Virus: Introduction and Epidemiology. Cold Spring Harbor perspectives in medicine. 2015;5(7):a021576. Epub 2015/07/03. pmid:26134842; PubMed Central PMCID: PMCPMC4484953.
- 7. Souto FJD. Distribution of hepatitis B infection in Brazil: the epidemiological situation at the beginning of the 21 st century. Revista da Sociedade Brasileira de Medicina Tropical. 2016;49:11–23. pmid:26689276
- 8. Elazar M, Koh C, Glenn JS. Hepatitis delta infection—Current and new treatment options. Best Pract Res Clin Gastroenterol. 2017;31(3):321–7. pmid:28774414.
- 9. Braga WS, de Oliveira CM, de Araujo JR, Castilho Mda C, Rocha JM, Gimaque JB, et al. Chronic HDV/HBV co-infection: predictors of disease stage—a case series of HDV-3 patients. Journal of hepatology. 2014;61(6):1205–11. Epub 2014/06/07. pmid:24905491.
- 10. Paraná R, Schinoni MI. Implementation and Impact of HAV and HBV Vaccination Programs in South America. Current Hepatitis Reports. 2013;12(4):305–11.
- 11. Cicero MF, Pena NM, Santana LC, Arnold R, Azevedo RG, Leal ES, et al. Is Hepatitis Delta infections important in Brazil? BMC Infect Dis. 2016;16(1):525. Epub 2016/10/01. pmid:27686363; PubMed Central PMCID: PMCPMC5041555.
- 12. Goyal A, Murray JM. Dynamics of in vivo hepatitis D virus infection. Journal of theoretical biology. 2016;398:9–19. Epub 2016/03/26. pmid:27012516.
- 13. da Fonseca JCF. Eradication of Hepatitis B virus infection in the State of Amazonas. 2007.
- 14. Lempp FA, Urban S. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses. 2017;9(7):172. pmid:28677645; PubMed Central PMCID: PMCPMC5537664.
- 15. Grimm D, Thimme R, Blum HE. HBV life cycle and novel drug targets. Hepatol Int. 2011;5(2):644–53. pmid:21484123; PubMed Central PMCID: PMCPMC3090558.
- 16. Parana R, Vitvitski L, Pereira JE. Hepatotropic viruses in the Brazilian Amazon: a health threat. The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases. 2008;12(3):253–6. http://dx.doi.org/10.1590/S1413-86702008000300017 pmid:18833412.
- 17. Ropero Alvarez AM, Perez-Vilar S, Pacis-Tirso C, Contreras M, El Omeiri N, Ruiz-Matus C, et al. Progress in vaccination towards hepatitis B control and elimination in the Region of the Americas. BMC Public Health. 2017;17(1):325. pmid:28415981; PubMed Central PMCID: PMCPMC5392937.
- 18. Luna EJ, Veras MA, Flannery B, de Moraes JC, Vaccine Coverage Survey G. Household survey of hepatitis B vaccine coverage among Brazilian children. Vaccine. 2009;27(39):5326–31. Epub 2009/07/21. pmid:19616495.
- 19.
Hemming J. Change in the Amazon Basin: The frontier after a decade of colonisation: Manchester University Press; 1985.
- 20.
Kershenobich D. Hepatitis B: What is happening in Latin America? 4th Latin American Meeting on Treatment of Viral Hepatitis and HIV Co‐infection; São Paulo, Brazil2015.
- 21. Abara WE, Qaseem A, Schillie S, McMahon BJ, Harris AM. Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention. Annals of internal medicine. 2017. Epub 2017/11/22. pmid:29159414.
- 22. Zhao S, Xu Z, Lu Y. A mathematical model of hepatitis B virus transmission and its application for vaccination strategy in china. International journal of epidemiology. 2000;29(4):744–52. Epub 2000/08/03. pmid:10922354.
- 23. Williams JR, Nokes DJ, Medley GF, Anderson RM. The transmission dynamics of hepatitis B in the UK: a mathematical model for evaluating costs and effectiveness of immunization programmes. Epidemiology and infection. 1996;116(1):71–89. pmid:8626006; PubMed Central PMCID: PMCPMC2271247.
- 24. Zou L, Zhang W, Ruan S. Modeling the transmission dynamics and control of hepatitis B virus in China. Journal of theoretical biology. 2010;262(2):330–8. Epub 2009/10/14. pmid:19822154.
- 25. Goyal A, Murray JM. Roadmap to control HBV and HDV epidemics in China. Journal of theoretical biology. 2017;423:41–52. pmid:28442239.
- 26. Sellier PO, Maylin S, Brichler S, Bercot B, Lopes A, Chopin D, et al. Hepatitis B Virus-Hepatitis D Virus mother-to-child co-transmission: A retrospective study in a developed country. Liver international: official journal of the International Association for the Study of the Liver. 2017. Epub 2017/08/24. pmid:28834623.
- 27. Craxi A, Tine F, Vinci M, Almasio P, Camma C, Garofalo G, et al. Transmission of hepatitis B and hepatitis delta viruses in the households of chronic hepatitis B surface antigen carriers: a regression analysis of indicators of risk. Am J Epidemiol. 1991;134(6):641–50. pmid:1951268.
- 28. Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. International journal of epidemiology. 2005;34(6):1329–39. pmid:16249217.
- 29. Franco E, Bagnato B, Marino MG, Meleleo C, Serino L, Zaratti L. Hepatitis B: Epidemiology and prevention in developing countries. World J Hepatol. 2012;4(3):74–80. pmid:22489259; PubMed Central PMCID: PMCPMC3321493.
- 30.
WHO. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015.
- 31. Alexandre KV, Martins RM, Souza MM, Rodrigues IM, Teles SA. Brazilian hepatitis B vaccine: a six-year follow-up in adolescents. Mem Inst Oswaldo Cruz. 2012;107(8):1060–3. pmid:23295759.
- 32. Pham EA, Perumpail RB, Fram BJ, Glenn JS, Ahmed A, Gish RG. Future Therapy for Hepatitis B Virus: Role of Immunomodulators. Curr Hepatol Rep. 2016;15(4):237–44. pmid:27917363; PubMed Central PMCID: PMCPMC5112294.
- 33. Ayoub WS, Keeffe EB. Review article: current antiviral therapy of chronic hepatitis B. Alimentary pharmacology & therapeutics. 2011;34(10):1145–58. pmid:21978243.
- 34. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology (Baltimore, Md). 2016;63(1):261–83. Epub 2015/11/14. pmid:26566064.
- 35. Heidrich B, Yurdaydin C, Kabacam G, Ratsch BA, Zachou K, Bremer B, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87–97. Epub 2014/03/04. pmid:24585488.
- 36.
PAHO. Hepatitis B and C in the Spotlight. A public health response in the Americas, 2016. Washington, D.C, United States: 2016.
- 37. de Soarez PC, Sartori AM, de Andrade Lagoa Nobrega L, Itria A, Novaes HM. Cost-effectiveness analysis of a universal infant immunization program with meningococcal C conjugate vaccine in Brazil. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2011;14(8):1019–27. pmid:22152170.
- 38. Eckman MH, Kaiser TE, Sherman KE. The cost-effectiveness of screening for chronic hepatitis B infection in the United States. Clin Infect Dis. 2011;52(11):1294–306. pmid:21540206; PubMed Central PMCID: PMCPMC3097367.
- 39. Blatt CR, Bernardo NLMdC, Rosa JA, Bagatini F, Alexandre RF, Balbinotto Neto G, et al. An Estimate of the Cost of Hepatitis C Treatment for the Brazilian Health System. Value in Health Regional Issues. 2012;1(2):129–35. pmid:29702891
- 40. Chen GF, Wei L, Chen J, Duan ZP, Dou XG, Xie Q, et al. Will Sofosbuvir/Ledipasvir (Harvoni) Be Cost-Effective and Affordable for Chinese Patients Infected with Hepatitis C Virus? An Economic Analysis Using Real-World Data. PLoS One. 2016;11(6):e0155934. pmid:27276081; PubMed Central PMCID: PMCPMC4898683.
- 41. Wiens A, Lenzi L, Venson R, Pedroso ML, Correr CJ, Pontarolo R. Economic evaluation of treatments for chronic hepatitis B. Braz J Infect Dis. 2013;17(4):418–26. pmid:23849851.
- 42.
Ciancio A, Rizzetto M. Treatment of Hepatitis D. Viral Hepatitis: John Wiley & Sons, Ltd; 2013. p. 410–6.
- 43. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. Hepatology (Baltimore, Md). 2017;66(4):1296–313. pmid:28762522.
- 44. Villar LM, Amado LA, de Almeida AJ, de Paula VS, Lewis-Ximenez LL, Lampe E. Low prevalence of hepatitis B and C virus markers among children and adolescents. Biomed Res Int. 2014;2014:324638. pmid:25093164; PubMed Central PMCID: PMCPMC4100382.
- 45. Costa RM, Barbosa RS, Zucchi P. Expenditures in the health care system in Brazil: the participation of states and the Federal District in financing the health care system from 2002 to 2013. Clinics. 2015;70(4):237–41. PubMed PMID: PMC4418276. pmid:26017788
- 46. Hanus JS, Ceretta LB, Simoes PW, Tuon L. Incidence of hepatitis C in Brazil. Rev Soc Bras Med Trop. 2015;48(6):665–73. pmid:26676490.
- 47. Viana S, Parana R, Moreira RC, Compri AP, Macedo V. High prevalence of hepatitis B virus and hepatitis D virus in the western Brazilian Amazon. Am J Trop Med Hyg. 2005;73(4):808–14. Epub 2005/10/14. pmid:16222030.
- 48. Crispim MA, Fraiji NA, Campello SC, Schriefer NA, Stefani MM, Kiesslich D. Molecular epidemiology of hepatitis B and hepatitis delta viruses circulating in the Western Amazon region, North Brazil. BMC Infect Dis. 2014;14:94. Epub 2014/02/22. pmid:24555665; PubMed Central PMCID: PMCPMC3936897.
- 49. Castilho Mda C, Oliveira CM, Gimaque JB, Leao JD, Braga WS. Epidemiology and molecular characterization of hepatitis B virus infection in isolated villages in the Western Brazilian Amazon. Am J Trop Med Hyg. 2012;87(4):768–74. pmid:22908032; PubMed Central PMCID: PMCPMC3516333.
- 50. Braga WS, da Costa Castilho M, dos Santos IC, Moura MA, Segurado AC. Low prevalence of hepatitis B virus, hepatitis D virus and hepatitis C virus among patients with human immunodeficiency virus or acquired immunodeficiency syndrome in the Brazilian Amazon basin. Rev Soc Bras Med Trop. 2006;39(6):519–22. Epub 2007/02/20. pmid:17308694.
- 51. Braga WS, Castilho Mda C, Borges FG, Leao JR, Martinho AC, Rodrigues IS, et al. Hepatitis D virus infection in the Western Brazilian Amazon—far from a vanishing disease. Rev Soc Bras Med Trop. 2012;45(6):691–5. pmid:23295870.
- 52.
Zarrilli S. The case of Brazil. Geneva World Health Organization, 2000.
- 53.
Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, et al. Interim follow-up analysis in the REP 401 protocol: Functional control of HBeAg negative chronic HBV infection persists after withdrawal of combined therapy with REP 2139 or REP 2165, tenofovir disoproxil fumarate and pegylatedinterferon α-2a. The Liver Meeting 2017; Washington DC: AASLD; 2017.
- 54. Al-Mahtab M, Bazinet M, Vaillant A. Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS One. 2016;11(6):e0156667. Epub 2016/06/04. pmid:27257978; PubMed Central PMCID: PMCPMC4892580.
- 55. Patel R, Longini IM Jr., Halloran ME. Finding optimal vaccination strategies for pandemic influenza using genetic algorithms. Journal of theoretical biology. 2005;234(2):201–12. Epub 2005/03/11. pmid:15757679.
- 56.
WorldBank. Life expectancy at birth, total (years): The World Bank; 2016. Available from: http://data.worldbank.org/indicator/SP.DYN.LE00.IN?locations=BR.
- 57. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. Journal of hepatology. 2017;67(2):370–98. Epub 2017/04/22. pmid:28427875.
- 58. Nwokediuko SC. Chronic hepatitis B: management challenges in resource-poor countries. Hepatitis monthly. 2011;11(10):786–93. pmid:22224076; PubMed Central PMCID: PMCPMC3234575.
- 59. Andrade HH, Mello MB, Sousa MH, Makuch MY, Bertoni N, Faundes A. Changes in sexual behavior following a sex education program in Brazilian public schools. Cad Saude Publica. 2009;25(5):1168–76. pmid:19488501.
- 60. Fan R, Yin X, Liu Z, Liu Z, Lau G, Hou J. A hepatitis B-free generation in China: from dream to reality. Lancet Infect Dis. 2016;16(10):1103–5. pmid:27676339.
- 61. Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology (Baltimore, Md). 2010;52(6):2192–205. Epub 2010/10/05. pmid:20890947.
- 62. El Sherbini A, Omar A. Treatment of children with HBeAg-positive chronic hepatitis B: a systematic review and meta-analysis. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2014;46(12):1103–10. Epub 2014/09/10. pmid:25195086.
- 63. Komatsu H, Inui A, Fujisawa T. Pediatric hepatitis B treatment. Annals of Translational Medicine. 2017;5(3):37. PubMed PMID: PMC5326647. pmid:28251116
- 64. Xue MM, Glenn JS, Leung DH. Hepatitis D in Children. Journal of Pediatric Gastroenterology and Nutrition. 2015;61(3):271–81. PubMed PMID: 00005176-201509000-00005. pmid:25988557