Social Marketing : Planning Before Conceiving Preconception Care Social marketing approaches can help to shape the formation of and to create demand for preconception care services . This article describes four components of social marketing , often referred to as the 4 P 's , that should be carefully researched and set in place before a national effort to launch and sustain preconception care services is pursued . First , the product or package of services must be defined and adapted using the latest in scientific and health care standards and must be based on consumer needs and desires . Second , the pricing of the services in financial or opportunity costs must be acceptable to the consumer , insurers , and health care service providers . Third , the promotion of benefits must be carefully crafted to reach and appeal to both consumers and providers . Fourth , the placement and availability of services in the marketplace must be researched and planned . With the application of market research practices that incorporate health behavior theories in their exploration of each component , consumer demand for preconception care can be generated , and providers can take preconception care to the market with confidence . Introduction Preconception care -LRB- PCC -RRB- is a critical component of maternal and child health that does not currently have a strong foothold in our health care delivery system -LSB- 1 -- 3 -RSB- . A more detailed discussion of how preconception care supports preconception health -LRB- PCH -RRB- and ultimately healthy pregnancies and babies is found in the introduction of this volume . In order to market a health product or service , it is important to understand what people want or need before it is developed , and then to provide them with the opportunity to meet those needs in a way that is compelling to them and also improves a mutually beneficial outcome for patients and their providers : a healthy baby . Of course , unlike commercial products , the outcome of preconception care services -LRB- a healthy pregnancy and a healthy baby -RRB- , can not be guaranteed ; there are many factors that influence pregnancy and birth outcomes that are outside a mother or healthcare provider 's realm of control . Despite the risk of adverse outcomes , there is much a woman , her partner , and her health care provider can do together preconceptionally to optimize pregnancy and birth outcomes . Social marketing is defined as `` the application of commercial marketing technologies to the analysis , planning , execution , and evaluation of programs designed to influence voluntary behavior of target audiences in order to improve their personal welfare and that of society '' -LRB- 4 -RRB- . The social marketing process involves identifying an effective `` marketing mix '' of product , price , promotion , and place with the goal of offering an exchange that has clear and compelling benefits , minimal barriers , and an advantage over the competition . In plain language , that means setting up a situation so that future parents , health care professionals , and health insurers can all benefit and support a common goal of healthy women , healthy pregnancies , and healthy babies . To accomplish this , resources first need to be dedicated to conducting audience and market research using a systematic approach at all levels . Often , health behavior theories can be used to shape the development of new products or services as well as to evaluate their effectiveness in achieving intended outcomes . Table 1 lists some of the theories and frameworks that can be applied to addressing the 4 P 's of preconception care services -LRB- 5 -RRB- . Table 1Theories and frameworks applicable to guiding research on the 4 P 's of social marketing preconception care servicesMarketing componentTheory or frameworkFocus of the theory or frameworkRelevant constructs or conceptsProductSocial marketingThe application of marketing techniques to the design , implementation , and evaluation of programs designed to facilitate voluntary exchanges of mutual benefit and improved personal well-being and societal welfareFormative research ; Market segmentation ; Competitive analysisDiffusion of InnovationThe spread of new ideas , products , or services within a society or from one society to another ; focus on innovationRelative advantage ; Compatibility ; Complexity ; Trialability ; ObservabilityPriceSocial cognitive theoryThe interaction between personal factors , environmental factors , and human behaviorReciprocal determinism ; Behavioral capability ; Expectations ; Self-efficacy ; Observational learning ; ReinforcementsHealth belief modelThe perceptions of threat posed by a health problem , the benefits of avoiding the threat , and factors influencing the decision to actPerceived benefits ; Perceived barriers ; Cues to action ; Self-efficacyPromotionDiffusion of innovationThe spread of new ideas , products , or services within a society or from one society to another ; focus on diffusionCommunication channels ; Social systems/networksPrecaution adoption process modelThe journey from lack of awareness to action and maintenance in dealing with hazards ; acknowledge inherent riskUnawareness ; Unengaged ; Decision-making ; ActingPlaceCommunication theoryThe different types of communication that affect health behaviorMedia Exposure ; Media effects ; Agenda setting ; FramingNote . For easy-to-understand information about the theories , frameworks , constructs , and concepts listed in this table , go to http://www.nci.nih.gov/theory/pdf for a downloadable copy of NCI 's `` Theory at a Glance -- A guide for health promotion practice '' Viewing health care services as a business , and using language such as `` marketing '' and `` sales , '' may be uncomfortable to some who prefer to view the process of having a baby as a natural , emotional and deeply personal part of the human experience . However , the notion of providing preconception care as a service could very well benefit from a well-conceived and constructed social marketing research plan and execution that acknowledges and embraces the emotions of the patient and her partner . Thus , thinking about developing a social marketing plan to support preconceptional health care could help to ensure that babies are born with the best start in life . One example of how the business market has taken advantage of this type of opportunity is the development of a bank that preserves umbilical cord blood -LRB- UCB -RRB- . The original idea in 1988 was a not-for-profit resource bank of donated cord blood for those who might need it for transplantation purposes -LRB- 6 -RRB- . However , since that time , enterprising companies have created a market and generated the `` need '' for cord blood storage for a couple 's own child -- even though the chances they will personally need it are roughly 1 in 10,000 . Companies who forecast a profit in this service use direct marketing strategies to expectant couples through diaper companies and magazine subscriptions . Attempts to patent the cryopreservation processes and limit competition have raised legal , ethical and clinical questions -- but the market to sell the idea of cord blood collection and preservation is lucrative and the demand is increasing -LRB- 7 -RRB- . Advocates of preconception care can learn important lessons from the UBC preservation business marketing executives who market , sell and provide services to a similar audience . Product Preconception care -LRB- PCC -RRB- is the product or concept we are trying to `` sell '' as a precursor for assuring PCH : The need for PCC is well-supported by research in the health field -LRB- 1 , 8 , 9 -RRB- . The product has been described in a number of publications as including a `` bundle '' of services most often including screening of the following elements : reproductive history ; medications and potential teratogens ; environmental exposures ; age , family medical and genetic history ; infections and immunizations ; social habits and risk behaviors ; diet and exercise ; and any chronic medical conditions -LRB- 10 , 11 -RRB- . Preconception care is supported by a number of practitioner specialties -LRB- 1 , 12 , 13 -RRB- and was related to a Healthy People 2000 goal -LRB- 14 -RRB- . Whereas some aspects of PCC have more evidence linking them to improved outcomes -LRB- e.g. , folic acid for NTDs and glycemic control for diabetes -RRB- and others have less evidence -LRB- e.g. , genetic counseling and smoking cessation -RRB- , the need for a more integrated approach to health prior to conception enjoys a broad range of support -LRB- 15 -- 18 -RRB- . Nevertheless , there has been little support of PCC in a systematic manner in the US or other countries as a standard of care -LRB- 2 , 19 -- 21 -RRB- . A social marketing approach can provide an important support for that uptake by beginning with a critical first step -- defining the attributes of the `` product '' we are selling from a potential consumer 's point of view -- which involves formative research with consumers . Key questions for the research may include : what do women and their partners want , when are PCC services optimally delivered , and what needs would have to be met in order for women or couples to value PCC services ? This approach dictates that it is important to understand the perspective of the patient -LRB- and her partner -RRB- as more than just as consumers of health care services , but also by understanding their other perceived needs and desires in order to provide a satisfactory exchange . Couples may not view the decision to start a family as a medical decision , so this may be one reason the health care delivery system is more likely to be engaged some time after conception . In fact , couples may assess their financial readiness to start a family before their physical , emotional , or relationship readiness for this life-altering decision . The research that is an integral part of the social marketing process can help us to understand the decision-making dynamic -LRB- or lack thereof -RRB- that couples may engage in prior to conception . While only 50 % of pregnancies are planned in the U.S. , understanding how couples think about pregnancy may be a good place to start . Frishman suggests other `` windows of opportunity '' that could be explored among women including when women inquire about birth control , obtain negative pregnancy tests , or have recently delivered a baby -LRB- 22 -RRB- . Wallerstedt et al. suggest that preconceptional health promotion and interconceptional counseling may be even more beneficial for parents who have had previous perinatal or infant loss -LRB- 23 -RRB- . Social marketing research can help provide an understanding of the motivations and barriers for and against preconception care . A social ecological perspective -LRB- 24 -RRB- encourages program planners to look at multiple levels of influence : 1 -RRB- intrapersonal or individual level ; 2 -RRB- interpersonal or social level ; 2 -RRB- institutional or organizational level ; 4 -RRB- community level ; 5 -RRB- and public policy or societal level . A major corporation preparing to launch a new product for women who might become pregnant -LRB- e.g. , a new home pregnancy test -RRB- would never begin without spending substantial time and resources on understanding the target market and identifying the product attributes that will appeal to that market , while also knowing what the competitive environment is before they make investments in product development that might not have a profitable return . Product attributes can have a major impact on both the speed and extent of a product 's uptake by a target population . Rogers ' diffusion of innovation theory -LRB- 25 -RRB- identified a number of product attributes including relative advantage -LRB- is the product better than what it will replace ? -RRB- , compatibility -LRB- does the product fit with the intended audience ? -RRB- , complexity -LRB- is the product easy to use ? -RRB- , trialability -LRB- can the product be `` tried out '' before making a decision to purchase it ? -RRB- , and observability -LRB- are the results of the product visible and measurable ? -RRB- . Program planners can position their products effectively in the marketplace if they maximize their product 's appeal by addressing these important product attributes . Price The next aspect of social marketing research to increase the supply of and demand for preconception care is price -- defining the costs to patients , providers and insurers , measured in time and/or money , in order to have quality and timely preconception care . Once the product attributes have been defined and developed to address PCC services in a mutually satisfactory way for women , health care professionals and insurers , then appropriate pricing is vital to allow for uptake . Lowering the intangible -LRB- non-financial -RRB- costs to patients can be facilitated by using some common standards of social marketing : the most effective health messages often incorporate emotional connections and values to make behavior change more appealing . Also , the best social marketing approaches make it easy for people to make changes that the service providers want them to -- in this case in order to be healthy , and have a healthy pregnancy and baby . In addition to appeal and ease , some marketers would say that a new product would have to have relative advantage over products currently in the marketplace . `` New and improved '' labeling does matter when a product is introduced . A product 's relative advantage can often be framed as more appealing and/or easier , but at its core it must meet a customer need or desire . Appealing and easy actions to improve health are perceived as less costly by the patient or customer . Social cognitive theory -LRB- 26 -RRB- which addresses the interaction between personal , environmental , and behavioral factors is commonly used to understand many facets of a person 's expectations of outcomes from performing a behavior , environmental contexts -LRB- helps and hindrances -RRB- related to the behavior , experiences in performing the behavior -LRB- positive or negative -RRB- , and efficacy -LRB- ability/confidence -RRB- in performing the behavior . These are just a few of the ways in which the pricing can build on the positive product attributes developed in the first step . It also helps that the outcome -- a healthy pregnancy and baby -- is a highly valued and very tangible benefit for those who want it . The pricing for a health care organization is more complicated . Cost-effectiveness studies and business case studies need to document how the organization 's PCC service costs compare with treatment of preventable health conditions . Balancing financial overhead and time pressures in these times of managed care may be a real challenge -- and particularly so for reaching women who may have unplanned pregnancies . The greatest challenge may be weighing the intangible costs and benefits against the financial costs : How much preconceptional folic acid counseling is worth a child being born without a lifelong disability like spina bifida ? How many smoking cessation sessions balance out the costs of a premature/low birth weight baby who might spend his first months of life in the NICU ? How many fewer patients might a health care professional have time to see and bill for when pregnancy counseling they do for people with genetic conditions takes up more time ? And what additional patient education messages , addressing chronic or acute health issues , are not being delivered during a regular well visit because the health care professional 's time is being used discussing preconception health issues ? The health care provider medical office may well not be the best and/or most efficient way to market preconception care services to consumers in many cases . The practicing physician may also not be the first or best person to deliver the preconception care message . The goal of a good pricing strategy is to find an effective and innovative way to reach the target market while reducing the costs to both the health care delivery system and the consumer . Promotion After the product has been defined as a generally acceptable package of PCC services , and the price to individual and organization is determined to be mutually beneficial , how can a social marketing approach diffuse it into common practice and social norms ? This is where the promotion comes into play among two key audiences : 1 -RRB- people who would like to be providers -LRB- or sellers -RRB- of the product and 2 -RRB- people who would be consumers -LRB- or buyers -RRB- of the product . Often , promotion is thought to focus solely on creating demand among consumers for a particular product , and the promotion process is what most people typically think of as marketing or advertising . However , whereas most businesses prefer to have products `` on the shelf '' to meet the needs of consumers proactively , consumers are more influential than ever before in demanding that a product appears on their vendor 's shelves . PCC could very well become a product that consumers themselves create demand for -- especially since the health care industry already sees the value of preconception care services but has not built a product offering that delivers what they believe to be important . Once the product and pricing attributes are developed , then promoting the product among potential buyers and sellers could be done using a number of communication theories that provide guidance on what types of communication messages and media vehicles -LRB- e.g. communication channels -RRB- can achieve in terms of exposure and effects . In fact , trade shows and product expositions are a major venue for new products to be introduced to businesses who sell products . Health care provider/insurer conferences , continuing medical education efforts , and medical school training could be venues for promoting PCC services among potential providers -LRB- 27 -RRB- . Because the product attributes have already been defined as a benefit , and pricing has been addressed in the previous step , promotion should be a matter of convincing both buyers and sellers that they are acting in their own best interests . After promotion has helped to generate consumer demand for the product , PCC is an opportunity for current health care professionals , insurers and those in the business of health to expand their services -- as in a classic new product offering . An important way for organizations to justify offering these services is to demonstrate an immediate benefit -LRB- perhaps in sales of other products and services -RRB- in addition to longer term benefits -LRB- perhaps fewer complicated pregnancies , lower malpractice premiums , fewer patients who need life-long care -RRB- . And of course , the actual benefits would be determined through a process of market research with stakeholders -- such as patients , health professionals and insurers -LRB- Table 2 -RRB- . Addressing current barriers and how to overcome them is a major contribution of the promotion activities . Using innovative ways to promote preconception care services not only can be modified from general market promotions but also by taking advantage of existing opportunities to deliver tailored `` gateways/pathways '' to PCC services . These could vary from fertility treatment centers to other family planning arenas . Whether a woman is seeking to become pregnant or trying to avoid becoming pregnant -LRB- but preserving her options for the future -RRB- , she is a consumer who may be fertile ground , so to speak , for preconception care services . A challenging part of promoting PCC services will be figuring out how to move the thinking of a `` now-oriented '' consumer towards more `` future-oriented '' events ; especially because future outcomes could happen earlier than planned/anticipated . This promotion could take advantage of additional opportunities such as involving male partners and other influential people in women 's lives -- and also taking a lifelong approach to health -LRB- 13 , 28 -RRB- . Another challenge to promoting PCC services will be addressing the ethical aspects of promoting a product that can not guarantee outcomes : Not every woman who chooses and uses preconception care services will be able to have a healthy pregnancy or a healthy baby . In fact , it might even be the case that unhealthy women -LRB- e.g. those with chronic diseases or other medical conditions -RRB- are the first to want and use preconception care services because they know that their poor health status makes pregnancy a hazardous situation for themselves and their baby . The importance of recognizing hazards and taking precautionary actions to protect health , which are addressed in the precaution adoption process model -LRB- 29 -RRB- , may be relevant in promoting PCC services in a manner that acknowledges pregnancy as having inherent risk for both the mother and the unborn baby . Table 2Sample social marketing questions for selected stakeholders of preconceptional care servicesConsumersHealth care providersInsurersProduct -- What action must be taken by each audience -LRB- e.g. , product , behavior , or policy -RRB- What does PCC services need to look and feel like for consumers to want/use/demand them?What does PCC services need to look and feel like for busy health care providers to want to offer them?What does PCC services need to look and feel like for health insurers to want to cover this service?Pricing -- Why would they want to do it?What is the value of PCC services and what would they be willing to pay for them?What is the value for offering PCC services to patients and what would it cost to offer them?What is the return on investment for including PCC services as a covered service?Promotion -- How will each audience be told about the what , why , where , and how?How will PCC services be publicized and made available to consumers in a way that they are attractive , affordable , and accessible?How will PCC services be presented to health care providers so that they are willing and able to offer them?How will PCC services be presented to insurers so that they are willing and able to reimburse for them?Place -- Where can they do the action needed?What settings/locations are most acceptable , appropriate , and accessible for providing PCC services?What settings/locations are most acceptable , appropriate , and accessible for offering PCC services?What forums or conferences can instigate productive discussions about including PCC services as a covered expense ? Place It is useful to ask how PCC services could be placed , or distributed , to women across their reproductive lifespan in a manner that addresses social marketing 's call toward mutually satisfactory exchanges , and how the placement of PCC services could affect their delivery . What components of PCC might change across the life span -LRB- e.g. early health promotion/contraception/STD infection/vaccinations/others -RRB- ? The high level of unintended pregnancies in the US -- 40 -- 60 % for adults , 95 % for teens -LRB- 30 -RRB- -- is also a concern , because any approach that requires a self-selection into the audience will miss about half of the pregnancies . Some authorities have suggested a lifelong approach to preconceptional health -- throughout the lifespan of a women 's potential fertility -LRB- say , 10 -- 50 years of age -RRB- and an approach that may move women from one set of services and questions into another -LRB- 2 , 31 -RRB- . Social marketing can help by determining in the early phases what women and health care professionals want , and thus ensuring that supply can be ready when the demand is articulated . Health care professionals need to be involved in the design of those PCC services that they would deliver , and must do so in the context of what they would want to deliver -- and those they would benefit from . Women report that one of their most influential sources of health information is their own health care professional , who knows them , their medical history and their concerns -LRB- 32 -RRB- . Health care professionals and their medical staff may be the front line `` sales people '' for preconceptional care ; if doctors never offer their patients the opportunity to `` buy '' this product , it will go nowhere . Medical professionals who are trained on the benefits of the product -LRB- e.g. , by inclusion in medical school training and on medical board exams -RRB- and rewarded for using it -LRB- by reducing malpractice premiums for example -RRB- will find it more acceptable and worthwhile to integrate the practice into the time pressures of the busy medical office . Once a physician selection is made , patients visit for an acute problem , management of a chronic condition , and for routine checkups . Placement market research will help to define how PCC services may fit into each of these areas . This integrated vision of PCC could become part of the core training curricula for various medical professionals -- more than an option during continuing education . This strategic preparation for placement also ensures that when the increased demand from the consumer begins to be evident at the health care provider office , the medical professionals in that office will know how to respond to that demand , and have the knowledge and systems in place to do so . Existing `` bundles '' of services that can be prepackaged to respond to this demand have in some cases been developed -LRB- 33 , 34 -RRB- . If the research in the first phase shows that the busy medical office is not the best location for providing PCC services , then alternate placement sites must be identified . Conclusion The best marketing and sales happen when the product has the qualities that a consumer wants and that a seller wants to provide . PCC must meet the needs and desires of patients , health professionals and insurers in order to be successfully adopted in the United States . For women and their families , that may mean believing that a healthy , wanted baby is in their future . For doctors , that may mean finding a way to give healthy women the preventive services they want and need while still dealing with the urgent care of their sick patients . For insurers it may mean a balance in service provision to meet both short and long term financial goals . But market research is needed to actually define exactly what the benefits are to each of those groups . And it is likely to be that the satisfactory exchange is more than just a purely medical application of clinical services . Consumers across the US are willing to spend $ 3.00 to drink what is essentially a 50 cent cup of coffee , but they are experiencing something more than the product 's primary attributes -LRB- e.g. , flavor , caffeine -RRB- but also the positive associations with the product -LRB- e.g. , funky , cool -RRB- . In the same way , consumers can tell us how they would like to experience preconception health care services -LRB- 35 -RRB- . All of us need to understand that if we market and sell it as the best experience possible , PCC could contribute to healthier babies , fewer medical treatment costs , and a healthy next generation that thinks about pregnancy in a whole different way .

B I O O O O B I B I O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

social marketing
preconception care
preconception health
behavior theories


Dipeptidyl peptidase IV inhibitors in diabetes : more than inhibition of glucagon-like peptide-1 metabolism ? Inhibitors of the protease dipeptidyl peptidase IV -LRB- DPP-IV -RRB- are promising new drugs for the treatment of type 2 diabetes . They are thought to act by inhibiting the breakdown of glucagon-like peptide-1 and , thereby , selectively enhancing insulin release under conditions when it is physiologically required . These drugs are selective for DPP-IV , but the enzyme itself has a broad range of substrates other than glucagon-like peptide-1 . Other high affinity substrates of DPP-IV including peptide YY may also play a role in the regulation of energy homeostasis . Moreover , DPP-IV is also known as CD26 and considered to be a moonlighting protein because it has a wide range of other functions unrelated to energy homeostasis , e.g. in immunity . The potential role of DPP-IV inhibition on substrates other than glucagon-like peptide-1 in diabetes patients remains to be elucidated . Glucagon-like peptide-1 -LRB- GLP-1 -RRB- is a hormone which is released following meals and stimulates insulin release from the pancreas . Its effects are terminated by breakdown by the enzyme dipeptidyl peptidase IV -LRB- DPP-IV -RRB- . Therefore , inhibition of DPP-IV increases GLP-1 levels in the circulation and , hence , insulin release under conditions when it is needed , i.e. after a meal but not during fasting . Consequently , inhibition of GLP-1 inactivation is an insulinotropic principle which is unlikely to cause hypoglycaemia between meals . The lower risk for hypoglycaemic events as compared with other insulinotropic or insulin-sensitising agents makes DPP-IV inhibitors very promising candidates for a more physiological treatment of type 2 diabetes -LRB- Combettes and Kargar 2008 -RRB- . In recent years , a number of selective DPP-IV inhibitors such as vildagliptin and sitagliptin have been evaluated in clinical trials -LRB- Hermansen et al. 2007 ; Utzschneider et al. 2008 -RRB- and may have a future role in the treatment of type 2 diabetes -LRB- Combettes and Kargar 2008 -RRB- . In this issue of the journal , a novel DPP-IV inhibitor , ASP8497 , is being introduced , which is highly selective for DPP-IV as compared to other peptidases -LRB- Someya et al. 2008 -RRB- . However , DPP-IV itself is not selective for GLP-1 but has a wide range of other natural substrates -LRB- Boonacker and Van Noorden 2003 -RRB- . Therefore , we wish to highlight potential implications of this lack of selectivity of DPP-IV for the use of DPP-IV inhibitors in diabetes treatment . Another high affinity substrate of DPP-IV is peptide YY -LRB- PYY ; Mentlein et al. 1993 -RRB- . Whereas cleavage of GLP-1 by DPP-IV causes inactivation , cleavage of PYY yields the long C-terminal fragment PYY3 -- 36 , which is inactive at some but active at other subtypes of PYY receptors . Specifically , it converts the non-subtype-selective agonist PYY into a selective agonist at Y2 and Y5 receptors -LRB- Michel et al. 1998 -RRB- . Thus , DPP-IV does not inactivate PYY but , rather , qualitatively alters its biological activity . Indeed it has been reported that peripherally administered PYY3 -- 36 inhibits food intake in rats , whereas PYY is a potent central stimulator of food intake -LRB- Batterham et al. 2002 -RRB- . Given the role of obesity in type 2 diabetes , prevention of the formation of such an endogenous food intake inhibitor by a DPP-IV inhibitor may be undesirable . It has been proposed that the effects of peripherally administered PYY3 -- 36 on central nervous functions such as food intake may be mediated by excitation of afferent vagal fibres -LRB- Koda et al. 2005 -RRB- . However , the majority of subsequent rodent studies did not confirm inhibition of food intake by PYY3 -- 36 , particularly not following chronic administration -LRB- Boggiano et al. 2005 -RRB- . On the other hand , recent studies in non-rodents such as pigs -LRB- Ito et al. 2006 -RRB- or humans -LRB- Degen et al. 2005 ; Sloth et al. 2007a ; Sloth et al. 2007b -RRB- have reported reduced food intake upon peripheral administration of PYY3 -- 36 but typically , these effects were found only at relatively high concentrations . Moreover , the effect of PYY3 -- 36 on food intake was biphasic , depending on the duration of its administration -LRB- Parkinson et al. 2008 -RRB- . Two additional findings deserve consideration . Firstly , PYY3 -- 36 was reported to promote fat oxidation and ameliorate insulin resistance in mice even under conditions of chronic administration where it did not reduce food intake -LRB- van den Hoek et al. 2006 -RRB- . Secondly , PYY3 -- 36 was reported to lower plasma glucose levels even in the absence of alterations in circulating insulin levels -LRB- Bischoff and Michel 1998 -RRB- . Taken together , the presently available data on PYY3 -- 36 on food intake and metabolic parameters are not yet conclusive . However , it is clear that PYY3 -- 36 is largely formed by DPP-IV , raising the possibility that selective DPP-IV inhibitors may exert part of their effects by modulating the PYY/PYY3 -- 36 ratios . Therefore , it remains to be explored how possible effects on PYY cleavage contribute to metabolic effects of DPP-IV inhibitors in diabetic patients . Moreover , DPP-IV is not only a protease for substrates relevant to energy homeostasis , but it also has a range of additional functions -LRB- Boonacker and Van Noorden 2003 -RRB- . Therefore , it is considered to be a moonlighting protein . As a protease , it has several other substrates , and it also acts as a receptor and costimulatory protein in the immune system . In this regard , CD26 is considered to be an important regulator of T-cell function -LRB- Reinhold et al. 2008 -RRB- . These pleiotropic effects of DPP-IV or CD26 lead to numerous potential uses of its inhibitors other than type 2 diabetes including inflammatory diseases -LRB- Ohnuma et al. 2006 ; Reinhold et al. 2007 ; Thielitz et al. 2008 ; Thompson et al. 2007 -RRB- and , perhaps , certain types of cancers -LRB- Kikkawa et al. 2005 ; Thompson et al. 2007 -RRB- . Some of these effects may manifest as useful secondary actions when being used for the treatment of diabetic patients whereas others may manifest as adverse events . Most of these potential additional effects may not yet have manifested in the currently published diabetes literature , but it appears prudent to keep an eye on them .

B I I O O B O O O O O O O O O O O O O B I I O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O

dipeptidyl peptidase iv
peptide yy
diabetes
cd26


Hemangioblastomatosis in a patient with von Hippel-Lindau disease Case presentation A woman developed a cerebellar hemangioblastoma in 1991 at the age of 17 and von Hippel-Lindau disease was diagnosed . She underwent five craniotomies for recurrent hemangioblastoma . In 2001 she had a laminectomy for an intramedullar hemangioblastoma at C2-C3 level . In 2004 a renal cell carcinoma was found and a partial nephrectomy was performed . A few weeks after her last craniotomy in July 2005 she developed progressive right hemisensory disturbances and sensory ataxia . Spinal MRI showed leptomeningeal contrast enhancement around the entire spinal cord -LRB- see Figure -RRB- . The sensory ataxia progressed and she got tetraparesis , most severe proximally in her arms , especially myotome C4 . Although hemangioblastoma are not very radiosensitive , radiotherapy was started because of the rapid clinical deterioration . High-dose total neuraxis radiotherapy was considered to toxic . It was judged that most of her clinical complaints could be attributed to the cervical spine . Also the MRI showed the most severe lesions at the cervical region . Therefore she was treated from C1 to Th1 -LRB- 30 × 1.8 Gy -RRB- combined with dexamethasone -LRB- 2 × 8 mg -RRB- . During radiotherapy she developed also symptoms outside the radiotherapy field -LRB- thoracal radiculopathy -RRB- . As the main problem in VHL is uncontrolled angiogenesis by overexpressing VEGF and VEGF receptors , Thalidomide -LRB- 400 mg , later 600 mg -RRB- was added . Thalidomide inhibits angiogenesis induced by VEGF -LSB- 1 -RSB- . Despite the treatment she developed a total tetraplegia and died 3 months after diagnosis as a result of respiratory failure . This syndrome appears to result from delayed growth of subarachnoid tumor cells disseminated by surgery . Hemangioblastomatosis is also seen in hemangioblastoma patients without von Hippel-Lindau disease and it is thought that additional genes are likely to be the source of this malignant behaviour -LSB- 2 -RSB- .

O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O


Interferon and lamivudine vs. interferon for hepatitis B e antigen-positive hepatitis B treatment : meta-analysis of randomized controlled trials Aims To compare interferon monotherapy with its combination with lamivudine for hepatitis B e antigen -LRB- HBeAg -RRB- - positive hepatitis B treatment . Chronic hepatitis B is a common medical condition , affecting more than 400 million individuals worldwide , leading to hepatic inflammation and injury -LRB- 1 -- 4 -RRB- . This viral-triggered , immune-mediated condition predisposes those affected to cirrhosis and hepatocellular carcinoma , thus necessitating treatment -LRB- 1 -- 3 -RRB- . The treatment consists of individualized , single-agent therapy with interferon-α or nucleoside analogues . Unfortunately , this treatment fails to yield long-lasting outcomes in majority of the treated population , prompting the notion of their use in combination to enhance the therapeutic efficacy -LRB- 4 -- 8 -RRB- . The notion of combination therapy for chronic hepatitis B treatment has been previously examined , yielding inconclusive results -LRB- 9 -- 16 -RRB- . In our study , we aim to elucidate this topic comparing interferon monotherapy to its combination with the best-studied antiviral agent for that purpose , lamivudine . Furthermore , the focus of our analysis is hepatitis B e antigen -LRB- HBeAg -RRB- - positive patients , a subset of the patient population in which disease activity , risk of complications and the subsequent need of efficacious therapy are more pronounced . Methods Literature search and study design Two independent researchers conducted the literature search , study selection and data extraction , with any disagreements resolved by consensus among them . The researchers conducted a systemic literature search using the electronic databases MEDLINE -LRB- 1966 to January 2006 -RRB- , EMBASE -LRB- 1980 to June 2006 -RRB- , OVID -LRB- 1966 to January , week 3 , 2006 -RRB- and the Cochrane library clinical trials registry -LRB- issue 1 , 2007 -RRB- . The following keywords were used : ` Hepatitis B ' , ` Interferon ' , ` Lamivudine ' and ` combination therapy ' . In addition , a manual search using citations in previous publications was preformed . The following inclusion criteria were used : -LRB- i -RRB- study design : randomized controlled trials ; -LRB- ii -RRB- study population : HBeAg-positive patients ; -LRB- iii -RRB- intervention : interferon vs. interferon and lamivudine therapy . Our search was not restricted by language . The following exclusion criteria were used : -LRB- i -RRB- examining the nonadult population ; -LRB- ii -RRB- not reporting any of the primary efficacy measures as defined by the authors . When several publications pertaining to a single study were identified , the most recent and complete publication was used . The included studies were divided into two groups according to their use of conventional -LRB- CON -RRB- or pegylated -LRB- PEG -RRB- interferon-α , with patients within each group given interferon monotherapy , or interferon and lamivudine combination therapy . Data were extracted for study methodology and for the defined efficacy measures . Only data pertaining to the regimens in question were extracted , while data concerning other regimens were reviewed , and if found to be of significance to our study , were noted and discussed . Separate meta-analyses examining the defined efficacy measures were preformed . In addition , we compared the rates of sustained responses across groups aiming at the identification of a preferable regimen . Intention to treat analysis was used throughout this study , excluding histological response analysis , because of its low outcomes reporting rates . Efficacy measures and definitions End-of-follow-up -LRB- sustained -RRB- virological and biochemical response rates , and sustained HBeAg clearance and seroconversion rates were used as primary efficacy measures . Histological response , emergence of YMDD mutations , liver-related and all-cause mortality , and treatment safety were used as secondary efficacy measures . Virological response was defined as attainment of undetectable -LRB- or below 400 copies/mL -RRB- levels of hepatitis B virus DNA , as determined by polymerase chain reaction , which was previously found to be the most accurate measure of virological response monitoring -LRB- 2 -RRB- . Biochemical response was defined as normalization of alanine aminotransferase levels , HBeAg clearance as HBeAg disappearance and seroconversion as HBeAg antibodies appearance . Histological response was defined as a two-point reduction or increase in the histologic activity index score , signifying histological improvement and worsening respectively . Treatment safety was assessed using the occurrence rate of adverse effects necessitating treatment discontinuation . Study quality and homogeneity The included studies methodological quality was assessed using the Jadad quality scale -LRB- 15 -RRB- , an established composite score evaluating randomization , concealment and reporting of patient withdrawal and dropout rates , with scores ≥ 3 signifying high-quality studies . Heterogeneity was assessed for each analysis . Statistical analysis Quantitative meta-analyses were performed to assess differences between monotherapy and combination groups . Statistical analysis was performed and the Forest plots were generated using the comprehensive meta analysis ® software application , Version 2.0 -LRB- Biostat , Englewood , NJ , USA -RRB- . The odds ratios -LRB- OR -RRB- were calculated along with their , respective , 95 % confidence intervals -LRB- CI -RRB- and presented for each individual study as well as interferon type and across all studies . Subgroup analyses were presented using OR and their corresponding 95 % CI . Heterogeneity was assessed for each of the meta-analyses by means of Q-statistics and their corresponding P-values . Results Study selection and characteristics The literature search yielded 13 studies . Five studies were excluded on account of the following : -LRB- i -RRB- examining the nonadult population -LRB- n = 1 -RRB- ; and -LRB- ii -RRB- not examining or reporting the sustained response rates -LRB- n = 4 -RRB- . The eight remaining trials , involving 1321 patients , were included . Six trials used conventional interferon-α -LRB- n = 503 -RRB- -LRB- 16 -- 21 -RRB- and two trials used pegylated interferon-α -LRB- n = 808 -RRB- -LRB- 22 , 23 -RRB- . Two of the CON group trials exclusively studied treatment-naïve patients -LRB- 16 , 19 -RRB- , whereas the others studied a mixture of treatment-naïve and previously treated patients -LRB- 17 , 18 , 20 -- 23 -RRB- . The majority of patients were treated for a period of 1 year -LRB- n = 6 -RRB- -LRB- 16 -- 23 -RRB- , with some treated for 6 months -LRB- n = 2 -RRB- -LRB- 17 , 18 -RRB- . Sustained response rates were obtained at 6 months following treatment completion in most studies -LRB- n = 6 -RRB- -LRB- 17 , 19 -- 23 -RRB- , and at 40 or 54 weeks following treatment completion in some -LRB- n = 2 -RRB- -LRB- 16 , 18 -RRB- . The studies were of heterogeneous methodological quality -LRB- Jadad scores of 2 -- 5 -RRB- . All studies were published as full publications , with six studies published in English -LRB- 16 -- 19 , 22 , 23 -RRB- and two in Chinese -LRB- 20 , 21 -RRB- . One study used sequential therapy -LRB- 18 -RRB- , six used concurrent therapy -LRB- 16 , 17 , 19,21 -- 23 -RRB- and one used both -LRB- 20 -RRB- -LRB- see Tables 1 and 2 -RRB- . Table 2 Patient selection criteria of studies included in the meta-analysis Study Inclusion criteria Exclusion criteria Ayaz -LRB- 2006 -RRB- 1 . HBsAg positive for > 6 m and anti-HBeAg and HBsAg negative 2 . Presence of HBV DNA 3 . Evidence of inflammation on biopsy within 6 m of enrolment and ALT > 1.5 NL 1 . Previous treatment with INF , antiviral or immunosuppressive agents 2 . HIV , hepatitis C or D 3 . Other aetiologies of liver disease , alcohol intake > 40 g/day , decompensated liver disease or cancer 4 . No informed consent 5 . Pregnancy 6 . Any contraindications for INF use 7 . Leucocytes , neutrophil or platelet count of < 2500 , < 1000 and < 100 000/mL , respectively , or haemoglobin < 10 g/dL Song -LRB- 2004 -RRB- 1 . 19 -- 65 years old 2 . HBsAg positive for > 6 m and HBeAg positive 3 . HBV DNA > 500 000 copies/mL 4 . Evidence of inflammation by 2 NL < ALT < 500 Not reported Deng -LRB- 2003 -RRB- 1 . 15 -- 60 years old 2 . HBeAg and HBV DNA positive for > 6 m 3 . HBV DNA > 103 000 copies/mL 4 . Evidence of inflammation by ALT > 2 NL 1 . Immunosuppressive or antiviral therapy within 6 m 2 . Hepatitis of other aetiologies 3 . Decompensated liver disease 4 . Pregnancy or breast feeding Yalcin -LRB- 2002 -RRB- 1 . 16 -- 80 years old 2 . HBeAg and HBsAg positive 3 . HBV DNA positive 4 . Evidence of inflammation by histology and 1.5 < ALT < 10 NL , on three occasions within 6 m 1 . Previous INF therapy , antiviral or immunosuppressive therapy , or contraindication for INF therapy 2 . HIV , hepatitis C or D 3 . Decompensated liver disease or carcinoma 4 . Alcohol consumption > 40 g/day or other liver disease causes 5 . Pregnancy 6 . Leucocytes < 2500/mm3 , neutrophils < 1000/mm3 , platelets < 100 000/mm3 , or haemoglobin < 10g/dL 7 . Unable to obtain consent Cindoruk -LRB- 2002 -RRB- 1 . Adults 2 . HBeAg positive 3 . HBV DNA positive 4 . Evidence of inflammation by histology and by abnormal ALT levels for > 6 m 1 . Previous INF therapy 2 . HIV , hepatitis C or D 3 . Decompensated liver disease 4 . Diabetes , autoimmune , or other psychiatric or serious medical illness 5 . High alcohol intake or current drug abuse 6 . Pregnancy Schalm -LRB- 2000 -RRB- 1 . 16 -- 70 years old 2 . HBsAg and HBeAg positive at screening and at > 6 and > 3 m prior respectively 3 . HBV DNA > 500 000 copies/mL 4 . Evidence of inflammation by histology or persistently elevated ALT for > 3 m 1 . Contraindication to or previous INF therapy , or antiviral therapy within 6 m 2 . HIV , hepatitis C or D 3 . Decompensated liver disease 4 . Liver disease of other aetiology Lau -LRB- 2005 -RRB- 1 . Adults 2 . HBsAg positive for > 6 m and HBeAg positive 3 . HBV DNA > 500 000 copies/mL 4 . Evidence of inflammation on biopsy and 1 < ALT < 10 NL 1 . Treatment within 6 m 2 . HIV , hepatitis C or D 3 . Decompensated liver disease 4 . Serious medical or psychiatric illness 5 . Alcohol or drug use within 1 y 4 . Neutrophils < 1500 g/dL , platelets < 90 000/mm3 , or creatinine > 1.5 NL Janssen -LRB- 2005 -RRB- 1 . > 16 years old 2 . HBsAg positive for > 6 m and HBeAg positive on two occasions within 8 w of randomization 3 . Evidence of inflammation by two measurements of ALT > 2 NL within 8 w of randomization 1 . Antiviral or immunosuppressive therapy within 6 m 2 . HIV , hepatitis C or D 3 . Advanced liver disease or carcinoma 4 . Serious medical or psychiatric illness , or uncontrolled thyroid disease 5 . Substance abuse within 2 y 6 . Pregnancy or inadequate contraception 7 . Leucocytes < 3000/mm3 , neutrophils < 1800/mm3 , or platelets < 100 000/mm3 ALT , alanine aminotransferase ; HBV , hepatitis B virus ; HBsAg , hepatitis B surface antigen ; INF , interferon ; m , months ; NEG , HBeAg negative ; NL , upper limit of normal ; POS , HBeAg positive ; w , weeks ; y , years . Table 1 Characteristics of studies included in the meta-analysis Study n Study design Jadad score Therapy period Follow-up period Therapy regimen Conventional interferon-α Ayaz -LRB- 2006 -RRB- 68 RCT 2 12 m 6 m INF-α-2a 9 MU × 3/w with or without LMV 100 mg/day Song -LRB- 2004 -RRB- 90 RCT 2 12 m 6 m INF-α 3 MU × 3/w with or without LMV 100 mg/day Deng -LRB- 2003 -RRB- 62 RCT 2 48 w 24 w INF-α-1b 5 MU × 3/w with or without LMV 100 mg/day Yalcin -LRB- 2002 -RRB- 49 RCT 2 52 w 52 w INF-α-2b 10 MU × 3/w with or without LMV 100 mg/day Cindoruk -LRB- 2002 -RRB- 100 RCT 2 6 m 6 m INF-α 9 MU × 3/w with or without LMV 100 mg/day Schalm -LRB- 2000 -RRB- 144 RCT , DB 4 24 w 40 w INF-α 10 MU × 3/w with or without LMV 100 mg/day Pegylated interferon-α Lau -LRB- 2005 -RRB- 542 RCT , DB 5 48 w 24 w PegINF-α-2a 180 μg × 1/w with or without LMV 100 mg/day Janssen -LRB- 2005 -RRB- 266 RCT , DB 4 52 w 26 w PegINF-α-2b 100 μg × 1/w with or without LMV 100 mg/day DB , double blind ; INF , conventional interferon ; LMV , lamivudine ; m , months ; PegINF , pegylated interferon ; RCT , randomized controlled ; w , weeks . Sustained virological response Greater sustained virological response rates were observed for patients given combination as compared with monotherapy in the CON group -LSB- 61.1 vs. 35.4 % , OR = 11.7 , 95 % CI -LRB- 7.8 -- 17.6 -RRB- , P < 0.0001 -RSB- , and overall -LSB- 28.9 vs. 18.5 % , OR = 2.1 , 95 % CI -LRB- 1.3 -- 3.3 -RRB- , P = 0.002 -RSB- , although not in the PEG group -LSB- 12.2 vs. 11.8 % , OR = 1.1 , 95 % CI -LRB- 0.5 -- 2.3 -RRB- , P = 0.8 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 3.5 , P = 0.06 -RRB- -LRB- see Fig. 1 -RRB- . Fig. 1 Sustained virological response . CON , conventional interferon monotherapy vs. its combination with lamivudine ; PEG , pegylated interferon monotherapy vs. its combination with lamivudine . * Concurrent and sequential administration . Sustained biochemical response Greater sustained biochemical response rates were observed for patients given combination as compared with monotherapy in the CON group -LSB- 46.2 vs. 34.0 % , OR = 1.8 , 95 % CI -LRB- 1.2 -- 2.7 -RRB- , P = 0.007 -RSB- , although not in the PEG group -LSB- 37.9 vs. 38.1 % , OR = 1.0 , 95 % CI -LRB- 0.7 -- 1.3 -RRB- , P = 0.94 -RSB- , or overall -LSB- 36.1 vs. 36.7 % , OR = 1.2 , 95 % CI -LRB- 0.9 -- 1.5 -RRB- , P = 0.15 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 3.3 , P = 0.07 -RRB- -LRB- see Fig. 2 -RRB- . Fig. 2 Sustained biochemical response . CON , conventional interferon monotherapy vs. its combination with lamivudine ; PEG , pegylated interferon monotherapy vs. its combination with lamivudine . Sustained hepatitis B e antigen clearance No significant differences in sustained HBeAg clearance rates were observed between patients given combination and monotherapy in the CON group -LSB- 33.5 vs. 24.0 % , OR = 1.6 , 95 % CI -LRB- 0.9 -- 2.7 -RRB- , P = 0.09 -RSB- , PEG group -LSB- 30.6 vs. 34.4 % , OR = 0.8 , 95 % CI -LRB- 0.6 -- 1.1 -RRB- , P = 0.26 -RSB- and overall -LSB- 31.5 vs. 31.9 % , OR = 1.0 , 95 % CI -LRB- 0.7 -- 1.3 -RRB- , P = 0.88 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 2.6 , P = 0.11 -RRB- -LRB- see Fig. 3 -RRB- . Fig. 3 Sustained hepatitis B e antigen -LRB- HBeAg -RRB- clearance . CON , conventional interferon monotherapy vs. its combination with lamivudine ; PEG , pegylated interferon monotherapy vs. its combination with lamivudine . * Concurrent and sequential administration . Sustained seroconversion Greater sustained seroconversion rates were observed for patients given combination as compared with monotherapy in the CON group -LSB- 30.0 vs. 18.9 % , OR = 1.8 , 95 % CI -LRB- 1.1 -- 2.8 -RRB- , P = 0.01 -RSB- , although not in the PEG group -LSB- 27.9 vs. 31.0 % , OR = 0.9 , 95 % CI -LRB- 0.6 -- 1.2 -RRB- , P = 0.34 -RSB- , or overall -LSB- 28.7 vs. 27.1 % , OR = 1.1 , 95 % CI -LRB- 0.8 -- 1.4 -RRB- , P = 0.59 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 3.5 , P = 0.06 -RRB- -LRB- see Fig. 4 -RRB- . Fig. 4 Sustained seroconversion . CON , conventional interferon monotherapy vs. its combination with lamivudine ; PEG , pegylated interferon monotherapy vs. its combination with lamivudine . * Concurrent and sequential administration . Histological response Greater histological improvement rates were observed for patients given combination as compared with monotherapy in the CON group -LSB- 83.8 vs. 26.6 % , respectively , n = 1 , OR = 14.3 , 95 % CI -LRB- 3.3 -- 61.3 -RRB- , P < 0.001 -RSB- , although not in the PEG group -LSB- 48.1 vs. 53.4 % , respectively , n = 1 , OR = 0.8 , 95 % CI -LRB- 0.4 -- 1.7 -RRB- , P = 0.70 -RSB- , or overall -LSB- 61.4 vs. 47.9 % , respectively , n = 2 , OR = 1.7 , 95 % CI -LRB- 0.9 -- 3.3 -RRB- , P = 0.11 -RSB- . No significant differences in histological worsening rates were observed between patients given combination and monotherapy in the CON group -LSB- 0 vs. 6.7 % , respectively , n = 1 , OR = 0.23 , 95 % CI -LRB- 0.02 -- 3.3 -RRB- , P = 0.16 -RSB- , PEG group -LSB- 9.6 vs. 10.3 % , respectively , n = 1 , OR = 0.9 , 95 % CI -LRB- 0.3 -- 3.1 -RRB- , P = 0.9 -RSB- and overall -LSB- 6.0 vs. 9.6 % , respectively , n = 2 , OR = 0.6 , 95 % CI -LRB- 0.2 -- 1.9 -RRB- , P = 0.55 -RSB- . All-cause and liver-related mortality There were no reported deaths of any aetiology for either group -LRB- 0 % for both -RRB- . Safety No significant differences in safety rates were observed between patients given combination and monotherapy in the CON group -LSB- 1.6 vs. 0.9 % , OR = 1.7 , 95 % CI -LRB- 0.3 -- 9.0 -RRB- , P = 0.55 , n = 6 -RSB- , PEG group -LSB- 6.0 vs. 4.2 % , OR = 1.7 , 95 % CI -LRB- 0.9 -- 3.2 -RRB- , P = 0.12 , n = 2 -RSB- and overall -LSB- 4.1 vs. 2.7 . % , OR = 1.7 , 95 % CI -LRB- 0.9 -- 3.1 -RRB- , P = 0.10 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 0.001 , P = 0.98 -RRB- . YMDD mutation emergence Greater YMDD mutation emergence rates were observed for patients given combination as compared with monotherapy in the PEG group -LSB- 4.0 vs. 0 % , OR = 18.1 , 95 % CI -LRB- 2.4 -- 136.6 -RRB- , P = 0.005 , n = 2 -RSB- and overall -LSB- 4.5 vs. 0 % , OR = 14.8 , 95 % CI -LRB- 2.8 -- 77.6 -RRB- , P = 0.001 -RSB- , although not in the CON group -LSB- 5.9 vs. 0 % , OR = 9.9 , 95 % CI -LRB- 0.5 -- 177.1 -RRB- , P = 0.12 , n = 1 -RSB- . Heterogeneity was assessed and not found to be a concern -LRB- Q = 0.11 , P = 0.74 -RRB- . Conventional interferon combination therapy vs. pegylated interferon monotherapy Excluding virological response -LSB- 61.1 vs. 11.8 % , OR = 11.7 , 95 % CI -LRB- 7.8 -- 17.6 -RRB- , P < 0.0001 -RSB- , no significant differences in rates of biochemical response -LSB- 46.2 vs. 38.1 % , OR = 1.4 , 95 % CI -LRB- 1.0 -- 1.9 -RRB- , P = 0.052 -RSB- , HBeAg clearance -LSB- 33.5 vs. 34.9 % , OR = 0.9 , 95 % CI -LRB- 0.6 -- 1.4 -RRB- , P = 0.77 -RSB- or seroconversion -LSB- 30.0 vs. 31.4 % , OR = 0.9 , 95 % CI -LRB- 0.7 -- 1.3 -RRB- , P = 0.73 -RSB- were observed between patients given combination therapy in the CON group and those given monotherapy in the PEG group . Significantly greater virological response rates were observed with monotherapy in the CON as compared with the PEG group -LSB- 35.4 vs. 11.8 % , OR = 4.1 , 95 % CI -LRB- 2.6 -- 6.4 -RRB- , P < 0.0001 -RSB- . Discussion The suboptimal outcomes of current hepatitis B therapies have prompted the notion of their use in combination to achieve a synergistic effect and decreased mutagenicity -LRB- 2 -RRB- . Furthermore , it has been suggested that the enhanced efficacy of the combination will allow for the dose reduction of its components , thus decreasing the risk of potential adverse effects -LRB- 2 -RRB- . In our study , we explored this notion in the subset of HBeAg-positive patients . Our study is the first to examine the combination of interferon and lamivudine for chronic hepatitis B treatment , pooling data from all pertinent randomized-controlled trials into meta-analysis . This analysis will aid in achieving evidence-based conclusions on the matter , resolving the controversy in its regard and directing future investigational efforts . In our analysis , we found pegylated interferon monotherapy to be of comparable efficacy to its combination with lamivudine , providing similar rates of sustained virological and biochemical responses , and HBeAg clearance and seroconversion -LRB- P = 0.66 , 0.94 , 0.26 and 0.34 respectively -RRB- . Furthermore , while the pegylated interferon trials predominantly involved treatment-naïve patients , analysis of previously treated patients within one of those studies yielded similar outcomes -LRB- 24 -RRB- . In contrast , the addition of lamivudine to conventional interferon resulted in superior sustained virological , biochemical and seroconversion rates -LRB- P < 0.001 , P = 0.007 , 0.01 and 0.09 respectively -RRB- , similarly observed with sequential and concurrent administration -LRB- 20 -RRB- . A similar trend was observed with HBeAg clearance rates , although the sample size was insufficient to detect this effect -LRB- P = 0.09 -RRB- . As with pegylated interferon , treatment-naïve patients comprised the majority of the studied population and to a greater extent . Nonetheless , a controlled , nonrandomized trial of previously treated patients reported similar outcomes -LRB- 25 -RRB- . These outcomes are corroborated by those of our histological analysis -LRB- P < 0.001 and P = 0.70 for histological improvement in the CON and PEG groups respectively -RRB- and by those of others -LRB- 26 -RRB- . Importantly , our analysis provides an explanation to the discordance between the combinations ' effectiveness with conventional and not with pegylated interferon , with lamivudine-induced mutagenicity suppressed with the former , while not with the latter -LRB- P = 0.12 , and 0.05 respectively -RRB- . Accordingly , two possible regimens emerged from our analysis : pegylated interferon monotherapy , and conventional interferon and lamivudine combination therapy . A comparison between the two found them to be of comparable efficacy -LRB- P > 0.05 -RRB- , with the exception of virological response -LRB- P < 0.001 -RRB- . That said , it is the authors opinion that this combinations ' favourable virological response should not prompt its use as the regimen of choice , as a greater portion of treatment-naïve and thus easier to treat patients , comprised the CON as compared with the PEG group , with three CON group studies exclusively examining this patient population -LRB- 16 , 17 , 19 -RRB- . Our hypothesis is further supported by the superior virological outcomes of conventional as compared with pegylated interferon monotherapy -LRB- P < 0.0001 -RRB- , which is in conflict with current knowledge -LRB- 27 -RRB- , and is easily explained by this hypothesis . Accordingly , we suggest that in comparable populations , pegylated interferon monotherapy is likely to be similarly or more efficacious than lamivudine and conventional interferon combination therapy . More so , the thrice-weekly injection therapy required with conventional interferon poses a risk of low-patient compliance rates -LRB- 1 -- 3 , 28 -RRB- , with the risk further exacerbated by the addition of a second agent . The weekly administration of pegylated interferon monotherapy is likely to alleviate this concern , while carrying similar economic costs -LRB- 29 -RRB- . Consequently , we conclude that pegylated interferon monotherapy is likely to be the treatment of choice for HBeAg-positive chronic hepatitis B , with this conclusion being supported by others -LRB- 27 -RRB- . That said , when conventional interferon therapy is considered , particularly in highly compliant patients , its combination with lamivudine should be entertained . Similarly , studies examining the HBeAg-negative hepatitis B population did not find the addition of lamivudine to pegylated -LRB- 30 -RRB- , or conventional -LRB- 31 -RRB- , interferon to be advantageous . In addition , while the superiority of the combination over lamivudine monotherapy was suggested in previous studies , this effect is likely to represent interferon 's greater inherent efficacy as compared with lamivudine , rather than the enhanced properties of the combination , as demonstrated in those very studies -LRB- 22 , 30 -RRB- . Our study contains several limitations . Firstly , our use of intention to treat analysis , the methodological heterogeneity of the included studies , and the heterogeneity of their treatment and follow-up protocols , may have introduced some inaccuracies in our analysis . Notably , while the PEG group comprised large , carefully planned , well-executed studies , the CON group involved smaller , lower quality ones , thus weakening our conclusions in its regard . Secondly , the absence of adequate controls precluded the authors from studying the subsets of treatment-naïve and previously treated populations . Those concerns , however , were alleviated by the low patient lost for follow-up rates , the lack of statistically significant heterogeneity across studies , the beneficial effects of the combination with conventional interferon across the measured indicators and the agreement between our conclusions and those of other studies . While the focus of our study was lamivudine and interferon combination therapy , a plethora of other combinations have been explored as well . Among those studied were combinations of interferon and various antiviral agents -LRB- 32 , 33 -RRB- , interleukin-12 -LRB- 34 -RRB- and prednisone -LRB- 35 -RRB- . All yielded disappointing results . Additionally , studies investigating various antiviral combinations resulted in conflicting outcomes -LRB- 36 -- 40 -RRB- . Those results indicate the need for further study , as the goal of a safe and efficacious therapy is yet to be attained . Conclusion Pegylated interferon-α monotherapy is the treatment of choice for HBeAg-positive chronic hepatitis B , with no added benefit with lamivudine addition . However , when conventional interferon therapy is considered , its combination with lamivudine should be entertained .

B O B O B O B I O O B I O O O O O O O O O O B O O O B O B O B I O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O B O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O B B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O B O O O O B O O O B O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O B O O O O B O O O B O B O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O B O B O O O O B O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O B O O O O B O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O B B B O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B B O O O O O O O O O O B O B O O O O O O O O O O B I O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O B B B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O O B B O O O O B O B O O O O

combination
hepatitis b
interferon
lamivudine
therapy