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<title>Hepatitis B Endemicity</title></titleStmt>

<publicationStmt><distributor>BASE and Oxford Text Archive</distributor>


<availability><p>The British Academic Spoken English (BASE) corpus was developed at the

Universities of Warwick and Reading, under the directorship of Hilary Nesi

(Centre for English Language Teacher Education, Warwick) and Paul Thompson

(Department of Applied Linguistics, Reading), with funding from BALEAP,

EURALEX, the British Academy and the Arts and Humanities Research Board. The

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The recordings and transcriptions used in this study come from the British

Academic Spoken English (BASE) corpus, which was developed at the

Universities of Warwick and Reading under the directorship of Hilary Nesi

(Warwick) and Paul Thompson (Reading). Corpus development was assisted by

funding from the Universities of Warwick and Reading, BALEAP, EURALEX, the

British Academy and the Arts and Humanities Research Board. </p></availability>




<recording dur="00:47:40" n="6473">


<respStmt><name>BASE team</name>



<langUsage><language id="en">English</language>



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<person id="sf0284" role="participant" n="s" sex="f"><p>sf0284, participant, student, female</p></person>

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<personGrp role="speakers" size="4"><p>number of speakers: 4</p></personGrp>





<item n="speechevent">Lecture</item>

<item n="acaddept">Biological Sciences</item>

<item n="acaddiv">ls</item>

<item n="partlevel">UG2</item>

<item n="module">Medical Virology</item>




<u who="nm0283"><kinesic desc="projector is on showing slide" iterated="n"/> okay as promised the lecture <pause dur="0.5"/> # now is looking at hepatitis B <pause dur="0.3"/> virus there are no handouts for the this lecture but the first paper <pause dur="0.4"/> in the list of references that i gave you <pause dur="0.6"/> # <pause dur="0.9"/> has actually got everything in that this lecture's going to talk about and more <pause dur="0.4"/> so that can act as the notes for this lecture if you want something else to read <pause dur="2.5"/> okay so what i'm going to do is to talk about hepatitis B virus <pause dur="0.3"/> and i'm going to talk about <pause dur="0.3"/> its epidemiology in the same way that i've talked about measles <pause dur="0.4"/> and hopefully explain why it's different <pause dur="2.6"/> <kinesic desc="changes slide" iterated="n"/> this work was done jointly with # <gap reason="name" extent="2 words"/> <pause dur="0.4"/> who <pause dur="0.7"/> i made the mistake one day as post-doc in the group <pause dur="0.6"/> # made the mistake one day of showing him my payslip so he went off to work in <pause dur="0.2"/> <trunc>c</trunc> computer industry <pause dur="0.7"/> # <pause dur="0.5"/> <gap reason="name" extent="2 words"/> who now heads the <pause dur="0.2"/> mathematical or the <trunc>immuni</trunc> # <trunc>e</trunc> epidemiology group <pause dur="0.7"/> at # <pause dur="0.3"/> # <gap reason="name" extent="1 word"/> <pause dur="0.6"/> # and and <gap reason="name" extent="1 word"/> who's still around part of the department <pause dur="2.3"/> <kinesic desc="changes slide" iterated="n"/>

so i'm going to give an introduction i'm going to talk about the biology epidemiology and current methods of control of hepatitis B <pause dur="1.4"/> talk about its global prevalence <pause dur="1.4"/> and then explain two particular epidemiological processes <pause dur="0.6"/> that are <trunc>u</trunc> # in some ways unique <pause dur="0.4"/> to <pause dur="0.7"/> or one of them is unique to hepatitis B <pause dur="0.5"/> and then show how that reduces equilibrium results # that are different from measles <pause dur="0.4"/> and the effects that that can have in terms of trying to control <pause dur="4.8"/><kinesic desc="changes slide" iterated="n"/> hepatitis B virus <pause dur="1.5"/> causes acute disease in a minority of infections so about twenty per cent of people who are infected <pause dur="0.5"/> actually develop <pause dur="0.4"/> acute hepatitis <pause dur="0.4"/> and a small very small proportion will actually die of it most people <pause dur="0.4"/> go through an asymptomatic infectious stage which can last about six months but they don't know they've got hepatitis B <pause dur="1.9"/> a proportion of individuals however will fail to clear that infection and will become carriers <pause dur="0.9"/> and that's where the serious consequences of infection occur <pause dur="0.5"/> because they

induce a high turnover of liver cells so the the hepatitis is killing the liver cells <pause dur="0.7"/> produces a high turnover <pause dur="0.3"/> and so cirrhosis and primary hepatic cancer <pause dur="0.5"/> or P-H-C <pause dur="0.3"/> are actually consequences of long term carriage of hepatitis B <pause dur="1.0"/> but people remain infectious as carriers for many decades many years <pause dur="0.8"/> yeah so <pause dur="0.5"/> there is a contrast between the acute phase that's months <pause dur="0.9"/> and the carriage phase which is years <pause dur="0.8"/> mm and remember duration of infectiousness <pause dur="0.4"/> has an important role to play in epidemiology <pause dur="2.5"/><kinesic desc="changes slide" iterated="n"/> hepatitis B virus is transmitted <pause dur="1.0"/> by lots of different routes it's a classic small community virus <pause dur="1.1"/> this virus has obviously been around in people for a long time and has evolved to live in small communities <pause dur="1.5"/> so it's transmitted horizontally <pause dur="0.6"/> by close contact although <pause dur="0.4"/> many of the exact mechanisms are unknown it's it's <pause dur="0.3"/> sort of close contact <pause dur="0.6"/> body fluid transmission <pause dur="0.8"/> from one person to another so sexual contact has an important role in <pause dur="0.7"/> in developed countries <pause dur="1.6"/> and also <pause dur="0.4"/>

intravenous and particularly used to be very bunch of blood borne diseases associated with tranfusions until all tranfusions started to be screened for <pause dur="0.7"/> # viral infection <pause dur="0.5"/> # <pause dur="0.4"/> but still in a medical setting <pause dur="0.9"/> # <pause dur="0.3"/> infection is quite common so <pause dur="0.7"/> one of the # <pause dur="0.2"/> target groups for vaccination in the U-K are <pause dur="0.2"/> health care workers so doctors and nurses are routinely vaccinated with hepatitis B <pause dur="0.4"/> because they're likely to come in <trunc>con</trunc> contact with people who are infected more than <pause dur="0.3"/> the rest of the population <pause dur="0.9"/> and then finally there's a vertical transmission component <pause dur="0.8"/> from mother to child <pause dur="4.0"/><kinesic desc="changes slide" iterated="n"/> the public health significance of hepatitis B <pause dur="0.4"/> is that it's a very common virus <pause dur="0.5"/> so there are at least three-hundred-million people who are carriers <pause dur="0.9"/> and because of the age at which people get infected especially <pause dur="0.3"/> # boys getting infected <pause dur="0.3"/> who then develop <pause dur="0.4"/> cancer and cirrhosis <pause dur="0.4"/> in their sort of between twenty and forty years old <pause dur="0.4"/> it has a <trunc>s</trunc> very significant economic impact because that's just when <pause dur="0.7"/>

people have got children and aged parents to support <pause dur="1.4"/> so its economic impact is actually slightly bigger than its <pause dur="0.6"/> health impact if you like <pause dur="0.5"/> so it does kill people but it kills a group <pause dur="0.5"/> <trunc>w</trunc> who are economically productive <pause dur="1.6"/> and the contrast <pause dur="0.3"/> or or # or the flip side of that is the fact that we do have a very safe <pause dur="0.4"/> cheap effective vaccines that you will have heard about already <pause dur="0.5"/> # available for hepatitis B <pause dur="0.5"/> so it is a potential <pause dur="1.0"/> target in terms of control <pause dur="0.5"/> # <pause dur="0.5"/> economically important <pause dur="0.2"/> health important <pause dur="0.4"/> with a a good way of controlling it <pause dur="4.0"/><kinesic desc="changes slide" iterated="n"/> now <pause dur="0.6"/> it turns out that the interesting thing about hepatitis B <pause dur="0.4"/> is that it varies greatly in terms of its prevalence <pause dur="1.4"/> so i'm going to contrast the Gambia <pause dur="0.5"/> which is a small <pause dur="1.1"/> elongated country in west Africa <pause dur="0.7"/> # with the Republic of Ireland so talking about the results of this # <pause dur="0.2"/> the study that i'd i mentioned # earlier this morning <pause dur="1.5"/> so in the Gambia about eighty per cent of people <pause dur="0.3"/> having been infected by the age ten it's a childhood viral

infection <pause dur="0.9"/> yeah much like rubella <pause dur="0.5"/> or mumps <pause dur="0.6"/> that children commonly get infected <pause dur="0.4"/> and the vast majority will be infected before the age of ten <pause dur="1.2"/> in the Republic of Ireland by contrast and and that goes for the U-K as well <pause dur="0.6"/> only one-half of a per cent of the total population has ever been infected <pause dur="1.7"/> so it's an enormous discrepancy <pause dur="3.3"/> yeah so you end up with a <trunc>c</trunc> in essentially two <pause dur="0.5"/> splits two paradigms if you like high endemicity <pause dur="0.7"/> common childhood infection <pause dur="0.5"/> low endemicity it's a rare <pause dur="0.4"/> principally adult infection <pause dur="0.7"/> and predominantly known via risk factors so the people in the in the developed world <pause dur="0.3"/> who get hepatitis B predominantly <pause dur="0.3"/> have the risk factors of high numbers of sexual partners or intravenous drug users <pause dur="0.8"/> yeah <pause dur="1.2"/> in developing countries <pause dur="0.3"/> high endemicity areas actually assigning the route of transmission <pause dur="0.3"/> is much more difficult because it's it's <pause dur="0.4"/> everyone's got it <pause dur="0.4"/> and it's ubiquitous <pause dur="2.3"/><kinesic desc="changes slide" iterated="n"/> so this figure illustrates this <pause dur="0.3"/> high endemicity low endemicity split <pause dur="0.8"/> that principally

the developing world <pause dur="0.6"/> so that is <pause dur="0.3"/> by and large sub-Saharan Africa <pause dur="0.5"/> south-east Asia <pause dur="0.8"/> # native <trunc>s</trunc> <pause dur="0.2"/> native <pause dur="0.4"/> Americans i guess in the Amazonian Basin <pause dur="0.6"/> # <pause dur="0.4"/> and Inuits <pause dur="0.2"/> Eskimos <pause dur="0.2"/> in northern <pause dur="0.5"/> America <pause dur="0.8"/> they these communities have very high endemicity <pause dur="1.2"/> yeah the rest of the world <pause dur="0.6"/> really doesn't <pause dur="2.6"/><kinesic desc="changes slide" iterated="n"/> and the interesting thing is that there is no obvious explanation for this <pause dur="0.8"/> you would like to think oh it's genetics <pause dur="0.5"/> yeah it must be something to do with the hosts <pause dur="0.4"/> however if you transfer people through immigration from a high endemicity area <pause dur="0.3"/> to a low endemicity area <pause dur="0.5"/> then after a generation <pause dur="0.5"/> they've actually got low endemicity <pause dur="0.2"/> infection so it's not not something to do with host genetics that makes people more susceptible <pause dur="1.5"/> it's not something to do with the virus that makes it more transmissible <pause dur="1.1"/> yeah <pause dur="0.8"/> viruses from sub-Saharan Africa are continually being <trunc>tr</trunc> introduced into the U-K but we don't have <pause dur="0.5"/> high endemicity <pause dur="0.2"/> situation in the U-K <pause dur="1.2"/> yeah <pause dur="0.5"/> there are no specific behaviours which

seem to be related <pause dur="1.2"/> yeah <pause dur="0.9"/> so the best current explanation <pause dur="0.4"/> is the transmission is somehow higher in endemic areas <pause dur="1.2"/> yeah <pause dur="4.5"/><kinesic desc="changes slide" iterated="n"/> but it's a very hand-wavy sort of way <pause dur="1.2"/> at least this explanation really relies on this basic reproduction number R-zero <pause dur="1.3"/> yeah <pause dur="2.2"/> that somehow there's a very small difference between the basic reproduction number in the U-K <pause dur="0.4"/> it's very low <pause dur="0.4"/> and the basic reproduction number in the Gambia it's a bit higher <pause dur="0.9"/> for some unspecified reason <pause dur="1.1"/> mm <pause dur="1.8"/><kinesic desc="changes slide" iterated="n"/> so this is a picture that you've seen before <pause dur="0.4"/> that somehow the U-K's basic reproduction number is way down here <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.8"/> yeah <pause dur="0.8"/> just enough <pause dur="0.6"/> to have one-half of one per cent of people infected <pause dur="1.1"/> yeah <pause dur="0.4"/> and that the Gambia <pause dur="0.4"/> is up here somewhere <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="1.5"/> but there's no explanation <pause dur="0.5"/> well no other explanation as to why <pause dur="0.3"/> there should be that difference <pause dur="1.6"/> yeah <pause dur="2.6"/> are there any questions <pause dur="7.4"/><kinesic desc="changes slide" iterated="n"/> okay so it varies greatly between countries between different communities <pause dur="0.9"/> mm <pause dur="0.3"/> however <pause dur="0.5"/> if you actually go to the country <pause dur="0.6"/> it varies greatly within the country as well <pause dur="2.0"/> so if you

go to two for example villages in Alaska <pause dur="0.9"/> same people <pause dur="0.8"/> genetically speaking <pause dur="0.6"/> same behaviour same culture <pause dur="0.6"/> then the the prevalence of carriage can vary between zero and twenty per cent <pause dur="1.6"/> so any explanation that you have <pause dur="0.4"/> about <pause dur="0.4"/> this variability <pause dur="0.3"/> has to include <pause dur="0.2"/> a local component <pause dur="0.3"/> in fact the local component is almost bigger than the <pause dur="0.5"/> national one international one <pause dur="1.6"/> yeah <pause dur="0.7"/> so in fact you would expect very little difference in basic reproduction numbers and basic transmission <pause dur="0.4"/> between neighbouring villages <pause dur="0.7"/> so the explanation about oh it's R-zero it's contact it's behaviour <pause dur="0.2"/> it's genetics <pause dur="0.4"/> completely falls down <pause dur="0.7"/> mm <pause dur="5.9"/><kinesic desc="changes slide" iterated="n"/> okay well why is that interesting well it's scientifically interesting <pause dur="0.7"/> but it's also interesting in terms of control <pause dur="0.9"/> what are we going to do about it <pause dur="1.2"/> at the moment barring some <pause dur="0.3"/> drugs which are still under trial but at the moment immunization is the only public health measure that we have <pause dur="0.7"/> yeah <pause dur="1.7"/> now there's very little point in discussing it when it

comes to countries like the Gambia quite clearly it's a childhood infection everyone's going to get hepatitis B <pause dur="0.5"/> let's vaccinate everybody <pause dur="1.1"/> yeah <pause dur="0.9"/> and the indication is that you don't need a very high coverage <pause dur="0.5"/> to actually control or eradicate the infection <pause dur="0.5"/> yeah <trunc>i</trunc> vaccination is quite clearly <pause dur="0.5"/> the best option for control <pause dur="1.6"/> but there is considerable discussion and i put discussion in inverted commas because it's actually downright argument <pause dur="0.6"/> considerable discussion over whether or not it's appropriate for something like the U-K <pause dur="0.9"/> low endemicity countries <pause dur="0.7"/> to vaccinate <pause dur="1.3"/> because only one person in two-hundred is actually going to get hepatitis B <pause dur="0.4"/> so you're going to be vaccinating a hundred-and-ninety-nine children <pause dur="0.6"/> for no reason whatsoever <pause dur="1.5"/> course what you'd like to do is to walk into a classroom at the age of <pause dur="0.2"/> children at the age of five and say right <pause dur="0.3"/> all those of you who are going to <pause dur="0.2"/> use intravenous drugs when you're older <pause dur="0.4"/><vocal desc="laughter" iterated="y" n="ss" dur="1"/> and have more than

five sexual partners a year could you please put your hand up and we'll vaccinate you but <pause dur="0.7"/> that doesn't happen <pause dur="0.8"/> so you'd have to vaccinate all children <pause dur="0.9"/> so there is a cost issue <pause dur="1.5"/> in terms of you're actually wasting a hundred-and-ninety-nine <pause dur="0.4"/> vaccine cases wasting <pause dur="0.9"/> in inverted commas in effect wasting them <pause dur="0.6"/> and there's also a safety issue in the sense that you don't really want to vaccinate people for something that they're not going to <pause dur="0.6"/> ever get a risk for having <pause dur="0.7"/> mm <pause dur="1.5"/> so <pause dur="1.0"/> if we could actually find a reason for this endemicity change this this low-high endemicity split <pause dur="0.5"/> it might help <pause dur="0.4"/> designing control programmes so at the moment in the U-K we have a targeted programme <pause dur="0.7"/> that is that we <trunc>vac</trunc> offer vaccination to people who have specific risk factors <pause dur="0.5"/> of multiple sexual partners intravenous drug use <pause dur="0.8"/> # but of course then you have to wait for them to have those risk factors before you can vaccinate them <pause dur="3.0"/><kinesic desc="changes slide" iterated="n"/> so <pause dur="0.8"/> hepatitis B immunization policy this is <pause dur="1.3"/> # <pause dur="0.6"/> a good reason

for buying into Microsoft <pause dur="0.2"/> computer products <pause dur="0.6"/> the Bill and Melinda Gates Foundation <pause dur="0.4"/> gives a vast amount of money more money <pause dur="0.2"/> than you can possibly imagine <pause dur="0.5"/> to <trunc>h</trunc> to help control <pause dur="0.5"/> vaccine preventable diseases like hepatitis B <pause dur="0.7"/> so this <pause dur="0.2"/> picture is well out of date now it's <pause dur="0.3"/> this is # from three years ago <pause dur="0.4"/> most of the world is coloured blue most of the world has now got routine immunization <pause dur="0.3"/> and a lot of it is being paid for <pause dur="0.7"/> by Bill and Melinda Gates <pause dur="0.6"/> the few countries that are refusing to adopt <pause dur="0.2"/> vaccination include the U-K <pause dur="0.4"/> Scandinavia <pause dur="0.4"/> and the Netherlands <pause dur="0.7"/> principally because of this reason of <pause dur="0.9"/> of <pause dur="0.2"/> not wanting to vaccinate children when they don't need to be <pause dur="0.8"/> but most of the rest of the world has got this universal vaccination of children <pause dur="2.3"/><kinesic desc="changes slide" iterated="n"/> so <pause dur="1.2"/> that's a kind of introduction <pause dur="1.3"/> so i'm now going to provide you with a better explanation for this variation in prevalence between communities <pause dur="1.4"/> yeah <pause dur="4.6"/><kinesic desc="changes slide" iterated="n"/> assesses the interplay between two separate epidemiological processes <pause dur="0.9"/> <trunc>wo</trunc> first is that the proportion

of people who develop carriage is highly age-dependent <pause dur="1.0"/> yeah <pause dur="2.6"/> if you are young <pause dur="0.5"/> and by that i mean <pause dur="0.4"/> the younger you are the say months old <pause dur="0.5"/> then your chances of becoming a carrier and infected than if you're an adult <pause dur="2.5"/> the second is that the average age of infection decreases <pause dur="0.5"/> the more infection there is and i <trunc>ta</trunc> touched on this earlier today that the more common the virus is in the population <pause dur="0.5"/> the earlier people will be when they first get infected <pause dur="1.4"/> yeah <pause dur="0.8"/> and because of the differing time scales <pause dur="0.7"/> in terms of acute infection versus carriage <pause dur="0.2"/> months versus decades <pause dur="0.5"/> carriers <pause dur="0.6"/> are more important in terms of transmission <pause dur="0.8"/> that a carrier will infect approximately five times more people <pause dur="0.4"/> than an acute case <pause dur="0.4"/> because of that length of time over which they're infectious <pause dur="2.0"/> so the average age of infection will go down <pause dur="0.6"/> the more carriers there are <pause dur="1.1"/> yeah <pause dur="2.4"/> does that make sense <pause dur="5.3"/> <kinesic desc="changes slide" iterated="n"/> okay just to give you some data to illustrate these

points <pause dur="0.6"/> this shows <pause dur="0.3"/> picture shows the probability of carriage <pause dur="1.6"/> on the vertical axis against age of infection in years on the horizontal axis <pause dur="0.8"/> each of the red crosses represents a <pause dur="0.2"/> single study <pause dur="0.7"/> where people looked at infection in an age in a group of of people <pause dur="0.5"/> and saw what percentage of them became carriers <pause dur="1.2"/> # and the circle around <pause dur="0.9"/> # each of these studies represents the size of the study so this study here <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.4"/> had about two-hundred people in it <pause dur="0.3"/> and this one here <kinesic desc="indicates point on slide" iterated="n"/> will have had <trunc>v</trunc> # <pause dur="0.3"/> you know far fewer people in it <pause dur="2.2"/> but you can see there is a clear relationship here whereabouts up here <pause dur="0.5"/> if somebody is infected at birth <pause dur="0.3"/> by their mother <pause dur="1.1"/> then they have about a ninety per cent chance of becoming a carrier <pause dur="2.9"/> and that percentage that risk or probability drops quite dramatically <pause dur="0.5"/> so that by the time you get to the age of ten <pause dur="0.5"/> you're talking about five per cent <pause dur="0.7"/> oh sorry <pause dur="0.7"/> fifteen per cent <pause dur="0.9"/> yeah <pause dur="0.6"/> and it's about five per cent for adults overall <pause dur="0.8"/> so there's a very strong age relationship <pause dur="1.3"/> yeah <pause dur="4.2"/>

<kinesic desc="changes slide" iterated="n"/> this is the relationship between the rate of infection <pause dur="0.9"/> the amount of virus that's there in principally carriers <pause dur="0.3"/> and the age at infection <pause dur="1.3"/> so the more <pause dur="0.2"/> infection there is <pause dur="0.2"/> yeah the <pause dur="0.4"/> if you <trunc>th</trunc> can think of the <trunc>s</trunc> numbers of carriers going up this axis <pause dur="0.6"/> the lower the average age at infection will be <pause dur="1.8"/> yeah <pause dur="1.9"/> so these two things <pause dur="0.3"/> interact <pause dur="0.3"/> ignore the equation <pause dur="2.5"/><kinesic desc="changes slide" iterated="n"/> so the more carriers you have <pause dur="0.8"/> the lower the average age at infection <pause dur="1.1"/><kinesic desc="changes slide" iterated="n"/> so the more carriers you will create <pause dur="1.3"/> which will give you more carriers <pause dur="1.1"/> which will mean that the average age at infection is lower so there's a positive feedback loop <pause dur="0.9"/> the lower the average age at infection <pause dur="0.2"/> the higher the numbers of carriers you create <pause dur="0.5"/> and so the higher the rate of infection and so the lower the average age at infection <pause dur="0.2"/> yeah <pause dur="4.8"/> can everyone see that there's this positive feedback <pause dur="1.1"/> created in hepatitis B <pause dur="0.4"/> by the fact that the probability of becoming a carrier <pause dur="1.5"/> is higher the younger you are

when you're infected <pause dur="3.9"/> yeah <pause dur="0.4"/> any <pause dur="3.0"/> confusion <pause dur="0.6"/> no <pause dur="3.4"/> <kinesic desc="changes slide" iterated="n"/> skip that one <pause dur="0.5"/> <vocal desc="clears throat" iterated="n"/> <kinesic desc="changes slide" iterated="n"/> skip that one <pause dur="2.1"/> okay so this positive feedback <pause dur="0.2"/> creates <pause dur="1.1"/> a difference a change in this <pause dur="2.1"/> equilibrium diagram that i showed you earlier remember in the <pause dur="0.4"/> equilibrium diagram i showed you before <pause dur="0.7"/> has the basic reproduction number determining <pause dur="0.5"/> a threshold for when infection <trunc>occu</trunc> can occur <pause dur="0.4"/> or when it can be sustained in a population <pause dur="1.2"/> and here you see this threshold <kinesic desc="indicates point on slide" iterated="n"/> down here <pause dur="0.8"/> yeah <pause dur="0.6"/> so for relatively low values of the basic reproduction number and low values <pause dur="0.6"/> or <trunc>n</trunc> small numbers of infected individuals <pause dur="0.7"/> you essentially have a U-K situation so this black line represents <pause dur="0.4"/> a developed country a U-K situation <pause dur="0.8"/> where the rate of infection is very low <pause dur="0.2"/> not many people have # hepatitis B <pause dur="1.1"/> that means the average age at infection is quite high <pause dur="0.5"/> because you have to live quite a long time

before you meet somebody who's got hepatitis B <pause dur="0.8"/> which means the chances of becoming a carrier are quite small <pause dur="1.2"/> yeah <pause dur="0.3"/> so it's essentially an adult infection <pause dur="3.5"/> this equilibrium up here <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="1.4"/> is the high endemicity paradigm <pause dur="1.6"/> everybody has hepatitis B which means that all children get hepatitis B <pause dur="0.3"/> which means that they become carriers <pause dur="0.4"/> and it's this positive feedback loop <pause dur="1.2"/> yeah <pause dur="2.3"/> so you have two endemic states a low one and a high one <pause dur="1.4"/> and what's interesting <pause dur="0.9"/> in some ways is that is that for regions of the basic reproduction number <pause dur="1.2"/> these two endemic states can coexist <pause dur="1.0"/> yeah <pause dur="1.4"/> so <pause dur="1.4"/><kinesic desc="changes slide" iterated="n"/> what you have is these arrows representing <pause dur="0.2"/> how the <sic corr="population">popsulation</sic> will change <pause dur="0.3"/> in terms of <pause dur="0.4"/> endemicity <pause dur="0.6"/> yeah when it's away from its equilibrium <pause dur="1.9"/> so you have two endemic states separated by this <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.3"/> red line which is an unstable boundary <pause dur="0.8"/> so if you're down <kinesic desc="indicates point on slide" iterated="n"/> here in the U-K <pause dur="1.0"/> and for some reason you increase the amount of hepatitis B <pause dur="0.4"/> to go above this unstable

boundary <pause dur="1.9"/> then you cross over into a high endemicity regime <pause dur="0.9"/> you've got enough infection <pause dur="0.4"/> to enable children to become infected to become carriers <pause dur="0.3"/> to start off this positive feedback loop <pause dur="0.4"/> so the amount of infection will then increase up to high endemicity <pause dur="1.5"/> yeah <pause dur="4.4"/> so these two endemic states come about because of this high positive feedback loop <pause dur="2.3"/> and they can coexist <pause dur="0.7"/> so there need be no reason why the Gambia is different from the U-K <pause dur="1.1"/> other than the fact that the Gambia has a high prevalence <pause dur="0.9"/> and the U-K has a low prevalence <pause dur="3.4"/> yeah <pause dur="1.8"/> somehow the Gambia started high and stay there <pause dur="0.5"/> and somehow we've ended up down here <pause dur="0.6"/> but there's there need be no other explanation <pause dur="1.4"/> yeah <pause dur="2.8"/> and i'm going to talk more about that <pause dur="0.5"/> or i'm going to try and explain that more in a minute <pause dur="0.9"/> the other feature from this picture <pause dur="0.9"/> is the fact that <pause dur="0.6"/> you can have viral <trunc>per</trunc> <pause dur="0.3"/> persistence in a population <pause dur="0.8"/> in a <trunc>p</trunc> <pause dur="0.2"/> in a population where it couldn't invade <pause dur="0.9"/> so where the basic reproduction

number is less than one <pause dur="1.9"/> yeah down here <pause dur="1.7"/><kinesic desc="indicates point on slide" iterated="n"/> if you introduce some infection <pause dur="1.3"/> basic reproduction number is less than one <pause dur="0.7"/> the change of transmission won't occur <pause dur="1.6"/> but if you introduce enough infection <pause dur="1.7"/> you actually cross into this high endemicity state <pause dur="1.6"/> so in ecological terms if you like <pause dur="0.3"/> what hepatitis B is doing is is <pause dur="0.4"/> changing the host population <pause dur="0.6"/> yeah it's it's making everyone <trunc>t</trunc> be a carrier so that the <trunc>be</trunc> can sustain itself <pause dur="0.3"/> in a population which it couldn't invade <pause dur="1.9"/> mm <pause dur="5.1"/> are there any questions <pause dur="7.8"/><kinesic desc="changes slide" iterated="n"/> okay so this is different <pause dur="0.5"/> because of this positive feedback means infection can exist in a population <pause dur="0.3"/> that it couldn't invade into <pause dur="0.9"/> yeah and there's more complicated relationship between R-zero and seroprevalence in other words <pause dur="0.6"/> the methods that i talked about earlier for looking at age serological profiles just wouldn't work <pause dur="1.7"/> yeah because if you're looking at a population of eighty per cent infected by age ten you'd say oh R-zero has to be quite big <pause dur="0.4"/> but in fact R-zero could be less than

one <pause dur="1.1"/> in the Gambia <pause dur="0.9"/> mm <pause dur="1.5"/> and it produces these two stable possibilities high and low endemicity <pause dur="0.4"/> which are both self-sustaining <pause dur="0.3"/> both stable <pause dur="0.9"/> and which one you're at depends on where you start from <pause dur="4.3"/><kinesic desc="changes slide" iterated="n"/> now i have to mention these but i'm not going to go into any detail <pause dur="0.5"/> this is all controlled by two important parameters <pause dur="0.8"/> one of which is the relative infectiousness of carriers <pause dur="0.8"/> so although carriers are infectious for a longer period of time than acute cases <pause dur="0.4"/> they are less infectious <pause dur="1.3"/> yeah <pause dur="3.0"/> the other <pause dur="0.3"/> parameter <pause dur="0.7"/> is something i've called F <pause dur="0.5"/> which is the proportion of infected adults that become carriers <pause dur="0.7"/> yeah <pause dur="0.6"/> now the reason i highlight these two parameters is because there isn't actually much data on these two <pause dur="1.7"/> yeah <pause dur="1.0"/> what data there is and i've showed it to you suggests the proportion of infected adults <pause dur="0.5"/> who become carriers is about five per cent but <pause dur="0.4"/> you know it could be <pause dur="0.8"/> as high as eight or it could be as low as three <pause dur="2.3"/><kinesic desc="changes slide" iterated="n"/> now whether or not these <pause dur="1.0"/> occur <pause dur="1.2"/> yeah and this is

this is looking at the F and alpha in this figure here <pause dur="0.6"/> whether or not this pattern occurs of this <pause dur="0.7"/> multiple equilibria <pause dur="1.3"/> depends very much on these two parameters <pause dur="1.2"/> so in this picture here <pause dur="0.5"/> i am <pause dur="0.6"/> varying this alpha and this F so the relative infectiousness of carriers <pause dur="0.4"/> and the proportion of adults who become carriers <pause dur="0.7"/> so the solid black line <pause dur="0.8"/> is the one that i showed you earlier that's just the the basic relationship between R-zero and seroprevalence <pause dur="0.6"/> this is the one i showed before <pause dur="0.5"/> yeah and these other <pause dur="0.3"/> lines are varying these parameters for which we have little information <pause dur="1.9"/> okay <pause dur="4.4"/> so another <trunc>r</trunc> result from this is that <pause dur="0.4"/> it's not just the fact that you can get these multiple endemicities but the fact is that they are very sensitive <pause dur="0.7"/> to the parameters that you choose <pause dur="1.3"/> so it might be that the Gambia <pause dur="0.4"/> is different from the U-K <pause dur="0.5"/> perhaps in terms of diet <pause dur="0.8"/> which somehow means that adults <pause dur="0.3"/> are just <pause dur="0.3"/> a little more likely to become carriers than <pause dur="0.8"/> than people who don't have that

diet in the U-K <pause dur="1.0"/> and the difference is so small <pause dur="0.3"/> that you can't measure it <pause dur="1.2"/> without doing large studies <pause dur="1.0"/> but in fact <pause dur="0.5"/> it has a big impact on the epidemiology <pause dur="1.5"/> yeah <pause dur="1.7"/> so it's a it's a phenomenon called criticality the the the <trunc>s</trunc> dynamic situation is critically dependent <pause dur="0.5"/> on some values of the parameters <pause dur="2.6"/> and actually measuring those parameters in the field is <kinesic desc="changes slide" iterated="n"/> very difficult <pause dur="3.5"/> okay what i'm going to do now is to kind of illustrate <pause dur="1.7"/> potentially how we could explain this endemicity <pause dur="2.1"/> so this <pause dur="0.4"/> figure here shows what happens <pause dur="0.5"/> if you take this system <pause dur="0.8"/> over a period of this case five-thousand years <pause dur="0.6"/> because hepatitis B carriage is is quite persistent <pause dur="0.3"/> it means that <pause dur="0.5"/> the time scales over which hepatitis B changes are quite long <pause dur="1.1"/> yeah <pause dur="0.7"/> but let's take <pause dur="0.2"/> so this just running over five-thousand years <pause dur="0.8"/> and i start off at some level of infection <pause dur="1.0"/> and there where each of the arrows occurs vertical arrows what i'm doing is i'm <pause dur="0.2"/> reducing the basic reproduction number <pause dur="1.6"/> okay <pause dur="4.9"/> let me go <pause dur="0.7"/> back <pause dur="3.3"/>

<kinesic desc="changes slide" iterated="n"/><kinesic desc="changes slide" iterated="n"/> i'm actually starting on here <pause dur="0.3"/> yeah <pause dur="0.2"/> so i'm starting at a value <kinesic desc="indicates point on slide" iterated="n"/> here <pause dur="0.8"/> yeah <pause dur="0.4"/> and then i'm reducing the basic reproduction number to allow the the <pause dur="0.4"/> the system to go to the next equilbrium <pause dur="1.6"/> <kinesic desc="changes slide" iterated="n"/><kinesic desc="changes slide" iterated="n"/> yeah <pause dur="0.2"/> so i'm going <kinesic desc="indicates point on slide" iterated="n"/> here down to the next equilibrium then i'm reducing the basic reproduction number again <pause dur="0.4"/> going down to the next equilibrium <pause dur="0.4"/> and reducing the basic reproduction number going to the next one <pause dur="0.3"/> and eventually it goes extinct <pause dur="1.1"/> yeah <pause dur="0.4"/> so i'm essentially moving down that lower curve <pause dur="1.5"/> yeah <pause dur="0.2"/> does that make sense <pause dur="7.4"/> <kinesic desc="changes slide" iterated="n"/> if i start just above <pause dur="0.2"/> that unstable equilibrium that red dotted curve in the equilibrium diagram <pause dur="0.7"/> i go up to the high equilibrium <pause dur="1.5"/> yeah <pause dur="0.6"/> so the difference in the starting point <pause dur="0.3"/> between those two <pause dur="0.5"/> is as small as you like <pause dur="0.6"/> yeah <pause dur="2.4"/> above it we go up below it you go down <pause dur="1.1"/> and here i reduce the basic reproduction number again <pause dur="0.7"/> and this

point here <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.2"/> between these two <pause dur="0.3"/> reductions of the basic reproduction number <pause dur="0.7"/> is something <pause dur="0.3"/> called a catastrophe <pause dur="0.5"/> yeah the technical term for it <pause dur="0.8"/> where a small change in a parameter produces a <pause dur="0.3"/> a very big result <pause dur="0.4"/> and essentially what's happening is i'm falling off <pause dur="0.4"/> the end of the high endemicity and dropping down to the low endemicity <pause dur="1.3"/> yeah <pause dur="1.3"/> so in these <pause dur="1.2"/> curves here <pause dur="0.3"/> if i change the basic reproduction number <pause dur="0.3"/> so that i just drop off the end <pause dur="0.8"/> then i get a very dramatic change <pause dur="0.4"/> in the <pause dur="1.3"/> proportion positive <pause dur="1.1"/> for a very small change in the parameter <pause dur="1.6"/> <kinesic desc="changes slide" iterated="n"/><kinesic desc="changes slide" iterated="n"/><kinesic desc="changes slide" iterated="n"/> yeah <pause dur="3.0"/> so does that make sense <pause dur="2.4"/><event desc="noise from computer" iterated="n"/> remember not to go backwards again <pause dur="1.9"/> i've never done it with loudspeakers on so <pause dur="2.0"/> any questions </u><pause dur="1.7"/> <u who="sf0284" trans="pause"> are those </u><u who="nm0283" trans="overlap"> yeah </u><u who="sf0284" trans="overlap"> two parameters defined in the journal <pause dur="0.2"/> or are they just </u><u who="nm0283" trans="overlap"> yes </u><u who="sf0284" trans="overlap"> <unclear>just</unclear> like <pause dur="0.4"/> they are </u><pause dur="0.2"/> <u who="nm0283" trans="pause"> they are

defined yeah <pause dur="6.3"/><kinesic desc="changes slide" iterated="n"/> so a very small change in the parameters <pause dur="0.4"/> or the starting point <pause dur="0.3"/> can lead to a large <pause dur="0.3"/> changes in outcomes <pause dur="0.7"/> yeah <pause dur="1.9"/> and these changes these these <pause dur="0.4"/> differences <pause dur="1.1"/> can be so small that in fact they're undetectable <pause dur="0.5"/> in most field studies <pause dur="1.7"/> so additional heterogeneity <pause dur="0.5"/> is potentially going to come from the fact <pause dur="0.5"/> that if you have populations that are in transition <pause dur="0.5"/> between one state and another <pause dur="1.0"/> yeah they're moving slowly <pause dur="0.7"/> they are in transition <pause dur="0.6"/> then <pause dur="0.2"/> you'll get additional heterogeneity <pause dur="0.4"/> so one thing i didn't point out <trunc>f</trunc> was that <pause dur="0.5"/> although we have high and low endemicity states <pause dur="0.4"/> sub-Saharan Africa and the U-K <pause dur="0.6"/> much of southern Europe and north Africa <pause dur="0.3"/> are <trunc>in</trunc> have intermediate <pause dur="0.3"/> epidemiology <pause dur="1.6"/> so this would suggest that in between <pause dur="0.7"/> yeah intermediate <pause dur="0.3"/> endemicity <pause dur="0.4"/> there are actually countries on their way <pause dur="0.2"/> from high to low potentially <pause dur="2.2"/> yeah <pause dur="1.3"/> if you look at a country like Tunisia <pause dur="0.3"/> you can actually see a <trunc>cl</trunc> almost a cline

of hepatitis B <pause dur="0.3"/> from south to north <pause dur="0.8"/> yeah that that you're actually seeing hepatitis B <pause dur="1.3"/> going down as you go north through the country <pause dur="1.5"/> mm <pause dur="0.5"/> so there's a sort of geographical variation which is perhaps due to <pause dur="1.4"/><kinesic desc="changes slide" iterated="n"/> this this <pause dur="0.6"/> transition from high to low <pause dur="6.6"/> okay so is everybody happy about that explanation for different epidemiologies <pause dur="3.4"/> okay what i want to do now <pause dur="0.7"/> is to talk about <pause dur="0.4"/> the consequences of this <pause dur="0.5"/> in terms of public health <pause dur="2.3"/> and the first is the fact that you're going to potentially have <pause dur="2.2"/> different epidemiological <pause dur="1.2"/> scenarios high or low endemicity <pause dur="0.5"/> in the same country <pause dur="0.6"/> yeah if if this is right there is no reason why we shouldn't have high endemicity in the U-K <pause dur="1.3"/> yeah <pause dur="0.3"/> the only reason we don't have high endemicity is because we don't have high endemicity <pause dur="1.4"/> but if we infected lots of children tomorrow <pause dur="0.9"/> and they became carriers <pause dur="0.6"/> that would create the situation where the other children would become infected and they would become carriers <pause dur="0.4"/> and so on <pause dur="0.5"/> yeah we'd move to high endemicity <pause dur="1.6"/>

so we can illustrate that by looking at <pause dur="1.1"/><kinesic desc="changes slide" iterated="n"/> the effect of <pause dur="1.3"/> introducing carriers into a population <pause dur="1.1"/> yeah <pause dur="1.1"/> so we start off at low endemicity <pause dur="1.6"/> introduce some carriers <pause dur="2.2"/><kinesic desc="changes slide" iterated="n"/> if we introduce <pause dur="2.0"/> enough <pause dur="0.6"/> to make it high but not to cross over the boundary we get a little epidemic <pause dur="0.2"/> of infection <pause dur="0.4"/> but it settles back down to the low equilibrium <pause dur="1.0"/><kinesic desc="changes slide" iterated="n"/> mm <pause dur="1.6"/> but if we cross the boundary <pause dur="0.7"/> and introduce enough carriers <pause dur="0.5"/> then we create this positive feedback <pause dur="0.3"/> which results in a <trunc>g</trunc> moving up to high endemicity <pause dur="1.7"/> mm <pause dur="1.3"/> so we're just crossing over that red dotted line on the equilibrium boundary <pause dur="1.5"/> so this potentially has important consequences <pause dur="0.5"/> when thinking about for example immigration <pause dur="1.4"/> and in fact bringing hepatitis B carriers <pause dur="0.4"/> into a low endemicity country <pause dur="0.3"/> might well create the possibility <pause dur="0.3"/> of moving to a high endemicity <pause dur="1.6"/> yeah <pause dur="0.6"/> or for example failure of blood tranfusion services to actually detect hepatitis B <pause dur="0.7"/> if we created lots of carriers <pause dur="0.6"/> then we might move into a situation of high endemicity <pause dur="2.9"/> so there is this

potential <pause dur="2.1"/> of moving to high endemicity <pause dur="1.5"/> now <pause dur="0.4"/> whenever you talk about immigration or mention that word it <pause dur="0.2"/> it <trunc>prod</trunc> usually produces a kind of <pause dur="0.6"/> # <pause dur="0.4"/> bistable response in itself <pause dur="1.3"/> there's a very # good paper i'm not sure if it's on the list but # there's the reference given there <pause dur="0.9"/> which actually turns this on its head and says well <pause dur="0.4"/> in fact the majority of carriers in the U-K <pause dur="0.4"/> do actually come from overseas they were infected <pause dur="1.2"/> overseas so they're they've emigrated to the U-K <pause dur="0.3"/> they've brought their hepatitis B carriage with them <pause dur="4.0"/> so in fact the most cost-effective policy <pause dur="0.5"/> for the Department of Health <pause dur="0.4"/> when it trying to deal with hepatitis B carriage in the U-K <pause dur="1.2"/> is to vaccinate people <pause dur="0.6"/> in the countries <pause dur="0.8"/> where immigration starts from <pause dur="2.1"/> yeah <pause dur="3.4"/> in terms of vaccination we shouldn't be vaccinating people in the U-K we should be vaccinating people outside <pause dur="0.4"/> because that's where our hepatitis B comes from <pause dur="1.4"/> so it turns round a <pause dur="0.5"/> a sort of an anti-immigration <pause dur="1.3"/>

argument <pause dur="0.4"/> into one that's much more positive in terms of <pause dur="0.6"/> sharing health care globally <pause dur="0.9"/> mm <pause dur="8.1"/><kinesic desc="changes slide" iterated="n"/> everyone chuckles when they read this paper and says oh yes that's a funny thing isn't it but i actually think that this is # a <pause dur="0.3"/> a very <pause dur="0.3"/> important idea <pause dur="0.6"/> # that sooner or later everyone's going to catch on to <pause dur="0.8"/> # that <pause dur="0.6"/> vaccination <pause dur="0.4"/> overseas in terms of of increasing global travel <trunc>incleepa</trunc> increasing globalization <pause dur="0.3"/> is going to be the most cost-effective way <pause dur="0.3"/> in which we control infection in this country <pause dur="5.0"/><kinesic desc="changes slide" iterated="n"/> okay the <trunc>f</trunc> <pause dur="0.6"/> the other <pause dur="0.8"/> consequence of this <pause dur="1.3"/> dual <trunc>end</trunc> # high-low endemicity <pause dur="0.3"/> dichotomy <pause dur="0.4"/> is the fact that if you have a drug that could cure carriage <pause dur="1.4"/> yeah you could use it as a public health tool <pause dur="1.1"/> now at the moment such a drug doesn't exist there are drugs which you can use to suppress <pause dur="0.4"/> viral replication <pause dur="0.4"/> if for example you're going to do some sort of # <pause dur="0.3"/> # blood # liver transplant <pause dur="0.7"/> # <pause dur="0.3"/> but resistance arises quite quickly to them <pause dur="0.3"/> so there isn't anything yet which we <pause dur="0.2"/> we have <pause dur="0.5"/> use

<trunc>al</trunc> you can use although there are <pause dur="0.2"/> <trunc>s</trunc> many things <pause dur="0.3"/> in the pipeline <pause dur="0.5"/> but let's suppose that we had something <pause dur="0.9"/> so we can actually start at high endemicity <pause dur="0.5"/><kinesic desc="changes slide" iterated="n"/> and we could reduce the numbers of carriers we could go out into the community and we could say right <pause dur="0.8"/> we're going to cure carriage <pause dur="0.9"/> everyone we can find <pause dur="1.2"/> if we remove that level of carriage from the population <pause dur="0.6"/> yeah to some degree <pause dur="0.7"/> it means that children would no longer potentially become infected as <trunc>ch</trunc> # become infected <pause dur="0.5"/> which means that they wouldn't create carriers <pause dur="0.3"/> so you would break this positive feedback <pause dur="1.2"/> <kinesic desc="changes slide" iterated="n"/> yeah <pause dur="0.4"/> <kinesic desc="changes slide" iterated="n"/> so again you get this bistability <pause dur="0.4"/> <kinesic desc="changes slide" iterated="n"/> effect that if you cross this threshold <pause dur="0.7"/> you reduce the level of carriage enough <pause dur="0.5"/> you can actually switch from high to low endemicity <pause dur="3.7"/> yeah <pause dur="5.7"/> now this is <pause dur="0.9"/> again quite novel because people think in terms of curing

carriage in terms of curing individuals <pause dur="1.0"/> preventing people getting cirrhosis and hepatic <pause dur="0.6"/> and primary hepatic cancer <pause dur="0.5"/> not <pause dur="0.5"/> in terms of a public health tool <pause dur="1.7"/> yeah <pause dur="0.8"/> but carriers have two roles one is that they are themselves <pause dur="0.4"/> in danger of of serious health consequences <pause dur="0.5"/> the second is that they are actually transmitting to other people <pause dur="1.4"/> mm <pause dur="5.3"/> are there any questions about that <pause dur="1.8"/> mm <pause dur="3.3"/><kinesic desc="changes slide" iterated="n"/> okay so we can potentially use <pause dur="0.5"/> cure of carriage as a public health tool <pause dur="1.2"/> yep <pause dur="0.8"/> theoretically you could do the same thing with behaviour change if you could just say to carriers right don't transmit <pause dur="0.7"/> yeah <pause dur="0.2"/> or reduce viral load <pause dur="0.2"/> in those carriers <pause dur="0.2"/> to a to an extent you don't actually have to cure them <pause dur="0.6"/> if you could reduce viral loads to an extent that they were no longer infectious it would have the same effect <pause dur="1.6"/> but one of the key things <pause dur="0.6"/> for this is in terms of thinking about eradication <pause dur="1.9"/> eradication through vaccination <pause dur="0.9"/> is <pause dur="0.5"/> the time scale for it is very much related to duration of infectiousness <pause dur="1.9"/>

and it took about two-hundred <pause dur="0.6"/> infection generations to eradicate smallpox <pause dur="1.0"/> yeah <pause dur="0.5"/> which is actually quite a small number when you think about it <pause dur="0.4"/> you start vaccinating against smallpox in a concerted effort to eradicate <pause dur="1.4"/> and from that <pause dur="0.3"/> that point there are only two-hundred further generations of transmission <pause dur="1.4"/> yeah <pause dur="1.1"/> but it's possible with smallpox because the duration of infectiousness <pause dur="0.4"/> is only measured in days or weeks <pause dur="2.7"/> carriers for hepatitis B can survive many decades <pause dur="0.8"/> so even if we said tomorrow right let's eradicate hepatitis B <pause dur="0.6"/> we're going to have to wait <pause dur="0.2"/> fifty or sixty years <pause dur="0.5"/> before those children who are <pause dur="0.3"/> carriers now <pause dur="1.0"/> yeah <pause dur="0.2"/> if they survive <pause dur="0.7"/> actually <pause dur="1.0"/> stopping carriers <pause dur="1.2"/> mm <pause dur="0.4"/> so two-hundred it may well be two-hundred generations <pause dur="0.4"/> in terms of eradication but if we use <pause dur="0.6"/> clearance of carriage as a public health tool <pause dur="1.8"/> then we can reduce that time scale a lot <pause dur="0.3"/> and it actually makes eradication of hepatitis B <pause dur="0.3"/> a feasible proposition <pause dur="6.7"/><kinesic desc="changes slide" iterated="n"/> okay <pause dur="0.2"/> what i'm going to do now is i'm going to

look at vaccination <pause dur="0.7"/> how does vaccination influence <pause dur="0.6"/> this picture <pause dur="0.8"/> yeah <pause dur="0.6"/> this is the same picture as i showed you before <pause dur="0.4"/> # except that rather than <pause dur="0.8"/> prevalence of infection up the vertical axis i've got proportion of carriers <pause dur="0.5"/> but you can see there's low endemicity high endemicity and this unstable boundary between them <pause dur="1.5"/> okay <pause dur="2.6"/> and then suppose we had two communities which i've labelled P and Q <pause dur="2.5"/> and these two communities are high endemicity <pause dur="1.1"/> and it would look very much as though <pause dur="0.5"/> in terms of field investigation anyway that they have the same endemicity <pause dur="1.3"/> yeah in actual fact they might have very different basic reproduction numbers for some reason <pause dur="0.6"/> but <pause dur="0.5"/> you know you wouldn't be actually be able to tell because everyone's infected because of this positive feedback <pause dur="1.5"/> so let's come along and let's vaccinate <pause dur="0.5"/> mm <pause dur="2.5"/> <kinesic desc="changes slide" iterated="n"/> at fifty per cent so what i'm doing now is all i'm vaccinating fifty per cent of all children that are born <pause dur="1.1"/><kinesic desc="changes slide" iterated="n"/> and what that does <pause dur="1.3"/>

is to <trunc>ch</trunc> shift the <trunc>epidemi</trunc> shift the equilibrium <pause dur="1.3"/> and it shifts them all to the right <pause dur="0.9"/> yeah <pause dur="1.5"/> which you shouldn't be surprised about <pause dur="0.7"/> because that means that <pause dur="0.4"/> now you need a <pause dur="0.4"/> for any particular <pause dur="0.5"/> # value you need a higher R-zero for the for the virus to survive <pause dur="1.6"/> but interestingly <pause dur="0.4"/> it shifts the low equilibrium <pause dur="0.2"/> faster <pause dur="1.6"/> in other words you can't use vaccination <pause dur="0.5"/> to move a population from high endemicity to low endemicity <pause dur="3.5"/> because this low equilibrium moves out of the way faster <pause dur="1.2"/> so you can't drop down <pause dur="0.4"/> from here <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.5"/> to there <kinesic desc="indicates point on slide" iterated="n"/> <pause dur="0.9"/> yeah <pause dur="2.4"/> what you can do though is to eradicate infection <pause dur="1.0"/> so in this case vaccinating at fifty per cent <pause dur="0.4"/> this population up <kinesic desc="indicates point on slide" iterated="n"/> here with a basic reproduction number of two <pause dur="0.5"/> yeah <trunc>i</trunc> <pause dur="0.4"/> numbers of carriers will go down <pause dur="1.0"/><kinesic desc="indicates point on slide" iterated="n"/> this population here <pause dur="0.2"/> the numbers of carriers <pause dur="0.3"/> will go down but they will only just cling on <pause dur="0.9"/> <kinesic desc="changes slide" iterated="n"/> if i vaccinate at seventy per cent <pause dur="1.4"/>

yeah <pause dur="0.3"/> then this population <kinesic desc="indicates point on slide" iterated="n"/> here with a basic reproduction number of one <pause dur="0.4"/> yeah <pause dur="1.7"/> we're now working on <kinesic desc="indicates point on slide" iterated="n"/> these lines <pause dur="0.7"/> would just <pause dur="0.5"/> drop down <pause dur="0.7"/> you will eradicate infection from that <kinesic desc="indicates point on slide" iterated="n"/> population <pause dur="0.4"/> but you won't eradicate it from <kinesic desc="indicates point on slide" iterated="n"/> this population because it's still got this <pause dur="0.4"/> high endemicity equilibrium supporting it <pause dur="2.2"/> mm <pause dur="4.1"/> does that make sense <pause dur="5.4"/> you're all too nervous about asking questions aren't you <pause dur="5.3"/> <vocal desc="laughter" iterated="y" n="ss" dur="1"/><kinesic desc="changes slide" iterated="n"/> okay so the effect of the immunization is that lower equilibra move faster than upper equilibria <pause dur="0.2"/> they're all shifting to the right <pause dur="0.6"/> so we can't use immunization <pause dur="0.6"/> to change the endemicity <pause dur="1.2"/> yeah <pause dur="1.7"/> but it enhances the bistability <pause dur="0.4"/> so it increases the usefulness <pause dur="0.5"/> of chemotherapy against carriers <pause dur="5.1"/> i haven't <pause dur="1.6"/> necessarily shown that result <pause dur="0.3"/> but the effect of of looking at these two together <pause dur="0.7"/> yeah there is a synergy <pause dur="0.2"/> in both curing carriage and vaccination <pause dur="0.8"/> yeah which enhances both <pause dur="4.9"/> <kinesic desc="changes slide" iterated="n"/> and i shall <kinesic desc="changes slide" iterated="n"/>

skip <pause dur="1.4"/> that picture <pause dur="1.2"/> mm <pause dur="11.2"/> okay so <pause dur="1.4"/> bringing things together to a conclusion <pause dur="3.0"/> because of this <pause dur="0.6"/> positive feedback effect and the age-related probability of becoming a carrier <pause dur="0.8"/> hepatitis B <pause dur="0.2"/> transmission dynamics contain <pause dur="0.7"/> potentially complicated <pause dur="0.3"/> and very non-linear features and by non-linear <pause dur="0.4"/> i mean that if you double R-zero you don't just double the amount of infection <pause dur="0.8"/> yeah <pause dur="0.6"/> if i were to halve <pause dur="0.5"/> the amount of contact i won't just halve the size of the public health problem <pause dur="1.3"/> and the small changes in environmental behaviour <pause dur="0.4"/> can have large consequences <pause dur="0.5"/> because of this feedback loop magnifying the effect of any differences <pause dur="1.9"/> and that immigration and and <pause dur="0.2"/> carriage cure or carriage infectiousness removal or <pause dur="0.5"/> whichever term you like <pause dur="1.2"/> are really public health problems or interventions <pause dur="0.7"/> they are <pause dur="0.7"/> # features of hepatitis B that we can actually use <pause dur="0.7"/> to help reduce the size of the problem <pause dur="0.7"/> and <pause dur="0.3"/> potentially bring in the possibility of eradication <pause dur="8.0"/><kinesic desc="changes slide" iterated="n"/> it

also raises the question of how <pause dur="0.6"/> general is this type of mechanism <pause dur="1.3"/> mm <pause dur="1.0"/> for example tuberculosis shows a very similar <pause dur="0.4"/> geographical trends <pause dur="1.2"/> yeah from north to south <pause dur="1.5"/> is there something in <pause dur="0.5"/> tuberculosis transmission <pause dur="0.6"/> which <pause dur="0.5"/> creates the same effect <pause dur="1.2"/> yeah <pause dur="3.1"/> in fact it turns out that you can get very similar results <pause dur="0.6"/> if you <trunc>lo</trunc> include the effect of dose response <pause dur="0.3"/> in particular the higher the dose of infection you get <pause dur="0.6"/> the more likely you're to be infected <pause dur="0.7"/> and the higher the <pause dur="0.3"/> dose of infection that you give <pause dur="2.3"/> yeah so you can have you have that kind of dose response you can end up with the same positive feedback <pause dur="0.8"/> that in one community you can have <pause dur="0.2"/> high doses giving rise to lots of people spreading viruses that give high doses <pause dur="0.3"/> to lots of virus <pause dur="0.8"/> and in another community you don't have that positive feedback you just have some low level infection low doses <pause dur="0.5"/> means that people are only infectious with low doses <pause dur="0.7"/> yeah <pause dur="1.1"/> so a kind of dose effect <pause dur="0.4"/> can produce the same split <pause dur="1.5"/>

yeah <pause dur="2.8"/> and one of my one of the third years is currently doing their project on <pause dur="0.7"/> looking at that effect <pause dur="0.6"/> # in particular for tuberculosis to whether there is a high-low dose split <pause dur="2.3"/> the other question general question is whether there's a role for demographic change <pause dur="1.6"/> now there is something called a demographic transition which i'll talk more about <pause dur="0.3"/> in <pause dur="0.4"/> B-P-H-D next year <pause dur="0.6"/> # for those who are interested <pause dur="1.1"/> and demographic transition <pause dur="0.2"/> is essentially the move from developing <pause dur="0.6"/> country demography <pause dur="0.5"/> to developed country demography <pause dur="0.7"/> and developing countries are typified by having <pause dur="0.6"/> lots of children <pause dur="0.4"/> yeah # <pause dur="0.5"/> perhaps fifty per cent of people in sub-Saharan Africa are under the age of fifteen <pause dur="0.8"/> # <pause dur="0.4"/> fairly large households <pause dur="0.6"/> # <pause dur="0.2"/> population growing <pause dur="0.9"/> to the <trunc>sti</trunc> state where we have in the developed world where we have far fewer children the population is by and large much older <pause dur="0.4"/> and households tend to be somewhat smaller <pause dur="1.9"/> well if there's a positive role <pause dur="0.2"/> or a strong role for hepatitis B

transmission within households <pause dur="1.1"/> yeah and particularly the fact that children play this critical role in terms of becoming carriers for hepatitis B <pause dur="0.9"/> then changing the demography <pause dur="0.3"/> changing household size <pause dur="0.4"/> and reducing the numbers of children in the population <pause dur="0.4"/> <trunc>m</trunc> reducing birth rates <pause dur="0.3"/> may well have an effect on the epidemiology <pause dur="1.7"/> so perhaps the the transition from high to low endemicity <pause dur="0.4"/> goes along with the demographic change <pause dur="0.7"/> that occurs from developing to developed countries <pause dur="1.1"/> mm <pause dur="1.7"/> so i would love to be able to go back two-hundred years in the U-K <pause dur="0.3"/> and take some sera <pause dur="0.4"/> and to look for hepatitis B because <pause dur="0.8"/> i think there is a strong possibility that <pause dur="0.4"/> two-hundred a hundred years ago <pause dur="0.5"/> we were a high endemicity country of hepatitis B <pause dur="1.8"/> but <pause dur="0.3"/> and we've lost that over the past <pause dur="0.3"/> hundred years through the <trunc>dem</trunc> through the demographic transition <pause dur="0.7"/> # but i'll i won't be able to do that so that is idle speculation