nm0283: okay as promised the lecture er now is looking at hepatitis B virus 
there are no handouts for the this lecture but the first paper in the list of 
references that i gave you er has actually got everything in that this 
lecture's going to talk about and more so that can act as the notes for this 
lecture if you want something else to read okay so what i'm going to do is to 
talk about hepatitis B virus and i'm going to talk about its epidemiology in 
the same way that i've talked about measles and hopefully explain why it's 
different this work was done jointly with er namex who i made the mistake one 
day as post-doc in the group er made the mistake one day of showing him my 
payslip so he went off to work in c-, computer industry er namex who now heads 
the mathematical or the immuni-, er e-, epidemiology group at er er namex er 
and and namex who's still around part of the department 
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 talk about its 
global prevalence and then explain two particular epidemiological processes 
that are u-, er in some ways unique to or one of them is unique to hepatitis B 
and then show how that reduces equilibrium results er that are different from 
measles and the effects that that can have in terms of trying to control 
hepatitis B virus causes acute disease in a minority of infections so about 
twenty per cent of people who are infected actually develop acute hepatitis and 
a small very small proportion will actually die of it most people go through an 
asymptomatic infectious stage which can last about six months but they don't 
know they've got hepatitis B a proportion of individuals however will fail to 
clear that infection and will become carriers and that's where the serious 
consequences of infection occur because they 
induce a high turnover of liver cells so the the hepatitis is killing the liver 
cells produces a high turnover and so cirrhosis and primary hepatic cancer or P-
H-C are actually consequences of long term carriage of hepatitis B but people 
remain infectious as carriers for many decades many years yeah so there is a 
contrast between the acute phase that's months and the carriage phase which is 
years mm and remember duration of infectiousness has an important role to play 
in epidemiology hepatitis B virus is transmitted by lots of different routes 
it's a classic small community virus this virus has obviously been around in 
people for a long time and has evolved to live in small communities so it's 
transmitted horizontally by close contact although many of the exact mechanisms 
are unknown it's it's sort of close contact body fluid transmission from one 
person to another so sexual contact has an important role in in developed 
countries and also 
intravenous and particularly used to be very bunch of blood borne diseases 
associated with tranfusions until all tranfusions started to be screened for er 
viral infection er but still in a medical setting er infection is quite common 
so one of the er target groups for vaccination in the U-K are health care 
workers so doctors and nurses are routinely vaccinated with hepatitis B because 
they're likely to come in con-, contact with people who are infected more than 
the rest of the population and then finally there's a vertical transmission 
component from mother to child the public health significance of hepatitis B is 
that it's a very common virus so there are at least three-hundred-million 
people who are carriers and because of the age at which people get infected 
especially er boys getting infected who then develop cancer and cirrhosis in 
their sort of between twenty and forty years old it has a s-, very significant 
economic impact because that's just when 
people have got children and aged parents to support so its economic impact is 
actually slightly bigger than its health impact if you like so it does kill 
people but it kills a group w-, who are economically productive and the 
contrast or or er or the flip side of that is the fact that we do have a very 
safe cheap effective vaccines that you will have heard about already er 
available for hepatitis B so it is a potential target in terms of control er 
economically important health important with a a good way of controlling it now 
it turns out that the interesting thing about hepatitis B is that it varies 
greatly in terms of its prevalence so i'm going to contrast the Gambia which is 
a small elongated country in west Africa er with the Republic of Ireland so 
talking about the results of this er the study that i'd i mentioned er earlier 
this morning so in the Gambia about eighty per cent of people having been 
infected by the age ten it's a childhood viral 
infection yeah much like rubella or mumps that children commonly get infected 
and the vast majority will be infected before the age of ten in the Republic of 
Ireland by contrast and and that goes for the U-K as well only one-half of a 
per cent of the total population has ever been infected so it's an enormous 
discrepancy yeah so you end up with a c-, in essentially two splits two 
paradigms if you like high endemicity common childhood infection low endemicity 
it's a rare principally adult infection and predominantly known via risk 
factors so the people in the in the developed world who get hepatitis B 
predominantly have the risk factors of high numbers of sexual partners or 
intravenous drug users yeah in developing countries high endemicity areas 
actually assigning the route of transmission is much more difficult because 
it's it's everyone's got it and it's ubiquitous so this figure illustrates this 
high endemicity low endemicity split that principally 
the developing world so that is by and large sub-Saharan Africa south-east Asia 
er native s-, native Americans i guess in the Amazonian Basin er and Inuits 
Eskimos in northern America they these communities have very high endemicity 
yeah the rest of the world really doesn't and the interesting thing is that 
there is no obvious explanation for this you would like to think oh it's 
genetics yeah it must be something to do with the hosts however if you transfer 
people through immigration from a high endemicity area to a low endemicity area 
then after a generation they've actually got low endemicity infection so it's 
not not something to do with host genetics that makes people more susceptible 
it's not something to do with the virus that makes it more transmissible yeah 
viruses from sub-Saharan Africa are continually being tr-, introduced into the 
U-K but we don't have high endemicity situation in the U-K yeah there are no 
specific behaviours which 
seem to be related yeah so the best current explanation is the transmission is 
somehow higher in endemic areas yeah but it's a very hand-wavy sort of way at 
least this explanation really relies on this basic reproduction number R-zero 
yeah that somehow there's a very small difference between the basic 
reproduction number in the U-K it's very low and the basic reproduction number 
in the Gambia it's a bit higher for some unspecified reason mm so this is a 
picture that you've seen before that somehow the U-K's basic reproduction 
number is way down here yeah just enough to have one-half of one per cent of 
people infected yeah and that the Gambia is up here somewhere but there's no 
explanation well no other explanation as to why there should be that difference 
yeah are there any questions okay so it varies greatly between countries 
between different communities mm however if you actually go to the country it 
varies greatly within the country as well so if you 
go to two for example villages in Alaska same people genetically speaking same 
behaviour same culture then the the prevalence of carriage can vary between 
zero and twenty per cent so any explanation that you have about this 
variability has to include a local component in fact the local component is 
almost bigger than the national one international one yeah so in fact you would 
expect very little difference in basic reproduction numbers and basic 
transmission between neighbouring villages so the explanation about oh it's R-
zero it's contact it's behaviour it's genetics completely falls down mm okay 
well why is that interesting well it's scientifically interesting but it's also 
interesting in terms of control what are we going to do about it at the moment 
barring some drugs which are still under trial but at the moment immunization 
is the only public health measure that we have yeah 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 let's vaccinate everybody yeah and the 
indication is that you don't need a very high coverage to actually control or 
eradicate the infection yeah i-, vaccination is quite clearly the best option 
for control but there is considerable discussion and i put discussion in 
inverted commas because it's actually downright argument considerable 
discussion over whether or not it's appropriate for something like the U-K low 
endemicity countries to vaccinate because only one person in two-hundred is 
actually going to get hepatitis B so you're going to be vaccinating a hundred-
and-ninety-nine children for no reason whatsoever course what you'd like to do 
is to walk into a classroom at the age of children at the age of five and say 
right all those of you who are going to use intravenous drugs when you're older 
[laughter] and have more than 
five sexual partners a year could you please put your hand up and we'll 
vaccinate you but that doesn't happen so you'd have to vaccinate all children 
so there is a cost issue in terms of you're actually wasting a hundred-and-
ninety-nine vaccine cases wasting in inverted commas in effect wasting them 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 ever get a risk for 
having mm so if we could actually find a reason for this endemicity change this 
this low-high endemicity split it might help designing control programmes so at 
the moment in the U-K we have a targeted programme that is that we vac-, offer 
vaccination to people who have specific risk factors of multiple sexual 
partners intravenous drug use er but of course then you have to wait for them 
to have those risk factors before you can vaccinate them so hepatitis B 
immunization policy this is er a good reason 
for buying into Microsoft computer products the Bill and Melinda Gates 
Foundation gives a vast amount of money more money than you can possibly 
imagine to h-, to help control vaccine preventable diseases like hepatitis B so 
this picture is well out of date now it's this is er from three years ago most 
of the world is coloured blue most of the world has now got routine 
immunization and a lot of it is being paid for by Bill and Melinda Gates the 
few countries that are refusing to adopt vaccination include the U-K 
Scandinavia and the Netherlands principally because of this reason of of not 
wanting to vaccinate children when they don't need to be but most of the rest 
of the world has got this universal vaccination of children so that's a kind of 
introduction so i'm now going to provide you with a better explanation for this 
variation in prevalence between communities yeah assesses the interplay between 
two separate epidemiological processes wo-, first is that the proportion 
of people who develop carriage is highly age-dependent yeah if you are young 
and by that i mean the younger you are the say months old then your chances of 
becoming a carrier and infected than if you're an adult the second is that the 
average age of infection decreases the more infection there is and i ta-, 
touched on this earlier today that the more common the virus is in the 
population the earlier people will be when they first get infected yeah and 
because of the differing time scales in terms of acute infection versus 
carriage months versus decades carriers are more important in terms of 
transmission that a carrier will infect approximately five times more people 
than an acute case because of that length of time over which they're infectious 
so the average age of infection will go down the more carriers there are yeah 
does that make sense okay just to give you some data to illustrate these 
points this shows picture shows the probability of carriage on the vertical 
axis against age of infection in years on the horizontal axis each of the red 
crosses represents a single study where people looked at infection in an age in 
a group of of people and saw what percentage of them became carriers er and the 
circle around er each of these studies represents the size of the study so this 
study here had about two-hundred people in it and this one here will have had v-
, er you know far fewer people in it but you can see there is a clear 
relationship here whereabouts up here if somebody is infected at birth by their 
mother then they have about a ninety per cent chance of becoming a carrier and 
that percentage that risk or probability drops quite dramatically so that by 
the time you get to the age of ten you're talking about five per cent oh sorry 
fifteen per cent yeah and it's about five per cent for adults overall so 
there's a very strong age relationship yeah 
this is the relationship between the rate of infection the amount of virus 
that's there in principally carriers and the age at infection so the more 
infection there is yeah the if you th-, can think of the s-, numbers of 
carriers going up this axis the lower the average age at infection will be yeah 
so these two things interact ignore the equation so the more carriers you have 
the lower the average age at infection so the more carriers you will create 
which will give you more carriers which will mean that the average age at 
infection is lower so there's a positive feedback loop the lower the average 
age at infection the higher the numbers of carriers you create and so the 
higher the rate of infection and so the lower the average age at infection yeah 
can everyone see that there's this positive feedback created in hepatitis B by 
the fact that the probability of becoming a carrier is higher the younger you 
are 
when you're infected yeah any confusion no skip that one skip that one okay so 
this positive feedback creates a difference a change in this equilibrium 
diagram that i showed you earlier remember in the equilibrium diagram i showed 
you before has the basic reproduction number determining a threshold for when 
infection occu-, can occur or when it can be sustained in a population and here 
you see this threshold down here yeah so for relatively low values of the basic 
reproduction number and low values or n-, small numbers of infected individuals 
you essentially have a U-K situation so this black line represents a developed 
country a U-K situation where the rate of infection is very low not many people 
have er hepatitis B that means the average age at infection is quite high 
because you have to live quite a long time 
before you meet somebody who's got hepatitis B which means the chances of 
becoming a carrier are quite small yeah so it's essentially an adult infection 
this equilibrium up here is the high endemicity paradigm everybody has 
hepatitis B which means that all children get hepatitis B which means that they 
become carriers and it's this positive feedback loop yeah so you have two 
endemic states a low one and a high one and what's interesting in some ways is 
that is that for regions of the basic reproduction number these two endemic 
states can coexist yeah so what you have is these arrows representing how the 
popsulation will change in terms of endemicity yeah when it's away from its 
equilibrium so you have two endemic states separated by this red line which is 
an unstable boundary so if you're down here in the U-K and for some reason you 
increase the amount of hepatitis B to go above this unstable 
boundary then you cross over into a high endemicity regime you've got enough 
infection to enable children to become infected to become carriers to start off 
this positive feedback loop so the amount of infection will then increase up to 
high endemicity yeah so these two endemic states come about because of this 
high positive feedback loop and they can coexist so there need be no reason why 
the Gambia is different from the U-K other than the fact that the Gambia has a 
high prevalence and the U-K has a low prevalence yeah somehow the Gambia 
started high and stay there and somehow we've ended up down here but there's 
there need be no other explanation yeah and i'm going to talk more about that 
or i'm going to try and explain that more in a minute the other feature from 
this picture is the fact that you can have viral per-, persistence in a 
population in a p-, in a population where it couldn't invade so where the basic 
reproduction 
number is less than one yeah down here if you introduce some infection basic 
reproduction number is less than one the change of transmission won't occur but 
if you introduce enough infection you actually cross into this high endemicity 
state so in ecological terms if you like what hepatitis B is doing is is 
changing the host population yeah it's it's making everyone t-, be a carrier so 
that the be-, can sustain itself in a population which it couldn't invade mm 
are there any questions okay so this is different because of this positive 
feedback means infection can exist in a population that it couldn't invade into 
yeah and there's more complicated relationship between R-zero and 
seroprevalence in other words the methods that i talked about earlier for 
looking at age serological profiles just wouldn't work 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 but in fact R-zero could be less than 
one in the Gambia mm and it produces these two stable possibilities high and 
low endemicity which are both self-sustaining both stable and which one you're 
at depends on where you start from now i have to mention these but i'm not 
going to go into any detail this is all controlled by two important parameters 
one of which is the relative infectiousness of carriers so although carriers 
are infectious for a longer period of time than acute cases they are less 
infectious yeah the other parameter is something i've called F which is the 
proportion of infected adults that become carriers yeah now the reason i 
highlight these two parameters is because there isn't actually much data on 
these two yeah what data there is and i've showed it to you suggests the 
proportion of infected adults who become carriers is about five per cent but 
you know it could be as high as eight or it could be as low as three now 
whether or not these occur yeah and this is 
this is looking at the F and alpha in this figure here whether or not this 
pattern occurs of this multiple equilibria depends very much on these two 
parameters so in this picture here i am varying this alpha and this F so the 
relative infectiousness of carriers and the proportion of adults who become 
carriers so the solid black line is the one that i showed you earlier that's 
just the the basic relationship between R-zero and seroprevalence this is the 
one i showed before yeah and these other lines are varying these parameters for 
which we have little information okay so another r-, result from this is that 
it's not just the fact that you can get these multiple endemicities but the 
fact is that they are very sensitive to the parameters that you choose so it 
might be that the Gambia is different from the U-K perhaps in terms of diet 
which somehow means that adults are just a little more likely to become 
carriers than than people who don't have that 
diet in the U-K and the difference is so small that you can't measure it 
without doing large studies but in fact it has a big impact on the epidemiology 
yeah so it's a it's a phenomenon called criticality the the the s-, dynamic 
situation is critically dependent on some values of the parameters and actually 
measuring those parameters in the field is very difficult okay what i'm going 
to do now is to kind of illustrate potentially how we could explain this 
endemicity so this figure here shows what happens if you take this system over 
a period of this case five-thousand years because hepatitis B carriage is is 
quite persistent it means that the time scales over which hepatitis B changes 
are quite long yeah but let's take so this just running over five-thousand 
years and i start off at some level of infection and there where each of the 
arrows occurs vertical arrows what i'm doing is i'm reducing the basic 
reproduction number okay let me go back 
i'm actually starting on here yeah so i'm starting at a value here yeah and 
then i'm reducing the basic reproduction number to allow the the the system to 
go to the next equilbrium yeah so i'm going here down to the next equilibrium 
then i'm reducing the basic reproduction number again going down to the next 
equilibrium and reducing the basic reproduction number going to the next one 
and eventually it goes extinct yeah so i'm essentially moving down that lower 
curve yeah does that make sense if i start just above that unstable equilibrium 
that red dotted curve in the equilibrium diagram i go up to the high 
equilibrium yeah so the difference in the starting point between those two is 
as small as you like yeah above it we go up below it you go down and here i 
reduce the basic reproduction number again and this 
point here between these two reductions of the basic reproduction number is 
something called a catastrophe yeah the technical term for it where a small 
change in a parameter produces a a very big result and essentially what's 
happening is i'm falling off the end of the high endemicity and dropping down 
to the low endemicity yeah so in these curves here if i change the basic 
reproduction number so that i just drop off the end then i get a very dramatic 
change in the proportion positive for a very small change in the parameter yeah 
so does that make sense remember not to go backwards again i've never done it 
with loudspeakers on so any questions 
sf0284: are those 
nm0283: yeah 
sf0284: two parameters defined in the journal or are they just 
nm0283: yes 
sf0284: just like they are 
nm0283: they are 
defined yeah so a very small change in the parameters or the starting point can 
lead to a large changes in outcomes yeah and these changes these these 
differences can be so small that in fact they're undetectable in most field 
studies so additional heterogeneity is potentially going to come from the fact 
that if you have populations that are in transition between one state and 
another yeah they're moving slowly they are in transition then you'll get 
additional heterogeneity so one thing i didn't point out f-, was that although 
we have high and low endemicity states sub-Saharan Africa and the U-K much of 
southern Europe and north Africa are in-, have intermediate epidemiology so 
this would suggest that in between yeah intermediate endemicity there are 
actually countries on their way from high to low potentially yeah if you look 
at a country like Tunisia you can actually see a cl-, almost a cline 
of hepatitis B from south to north yeah that that you're actually seeing 
hepatitis B going down as you go north through the country mm so there's a sort 
of geographical variation which is perhaps due to this this transition from 
high to low okay so is everybody happy about that explanation for different 
epidemiologies okay what i want to do now is to talk about the consequences of 
this in terms of public health and the first is the fact that you're going to 
potentially have different epidemiological scenarios high or low endemicity in 
the same country yeah if if this is right there is no reason why we shouldn't 
have high endemicity in the U-K yeah the only reason we don't have high 
endemicity is because we don't have high endemicity but if we infected lots of 
children tomorrow and they became carriers that would create the situation 
where the other children would become infected and they would become carriers 
and so on yeah we'd move to high endemicity 
so we can illustrate that by looking at the effect of introducing carriers into 
a population yeah so we start off at low endemicity introduce some carriers if 
we introduce enough to make it high but not to cross over the boundary we get a 
little epidemic of infection but it settles back down to the low equilibrium mm 
but if we cross the boundary and introduce enough carriers then we create this 
positive feedback which results in a g-, moving up to high endemicity mm so 
we're just crossing over that red dotted line on the equilibrium boundary so 
this potentially has important consequences when thinking about for example 
immigration and in fact bringing hepatitis B carriers into a low endemicity 
country might well create the possibility of moving to a high endemicity yeah 
or for example failure of blood tranfusion services to actually detect 
hepatitis B if we created lots of carriers then we might move into a situation 
of high endemicity so there is this 
potential of moving to high endemicity now whenever you talk about immigration 
or mention that word it it prod-, usually produces a kind of er bistable 
response in itself there's a very er good paper i'm not sure if it's on the 
list but er there's the reference given there which actually turns this on its 
head and says well in fact the majority of carriers in the U-K do actually come 
from overseas they were infected overseas so they're they've emigrated to the U-
K they've brought their hepatitis B carriage with them so in fact the most cost-
effective policy for the Department of Health when it trying to deal with 
hepatitis B carriage in the U-K is to vaccinate people in the countries where 
immigration starts from yeah in terms of vaccination we shouldn't be 
vaccinating people in the U-K we should be vaccinating people outside because 
that's where our hepatitis B comes from so it turns round a a sort of an anti-
immigration 
argument into one that's much more positive in terms of sharing health care 
globally mm 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 er a a very important 
idea er that sooner or later everyone's going to catch on to er that 
vaccination overseas in terms of of increasing global travel incleepa-, 
increasing globalization is going to be the most cost-effective way in which we 
control infection in this country okay the f-, the other consequence of this 
dual end-, er high-low endemicity dichotomy is the fact that if you have a drug 
that could cure carriage yeah you could use it as a public health tool now at 
the moment such a drug doesn't exist there are drugs which you can use to 
suppress viral replication if for example you're going to do some sort of er er 
blood er liver transplant er but resistance arises quite quickly to them so 
there isn't anything yet which we we have use 
al-, you can use although there are s-, many things in the pipeline but let's 
suppose that we had something so we can actually start at high endemicity and 
we could reduce the numbers of carriers we could go out into the community and 
we could say right we're going to cure carriage everyone we can find if we 
remove that level of carriage from the population yeah to some degree it means 
that children would no longer potentially become infected as ch-, er become 
infected which means that they wouldn't create carriers so you would break this 
positive feedback yeah so again you get this bistability effect that if you 
cross this threshold you reduce the level of carriage enough you can actually 
switch from high to low endemicity yeah now this is again quite novel because 
people think in terms of curing 
carriage in terms of curing individuals preventing people getting cirrhosis and 
hepatic and primary hepatic cancer not in terms of a public health tool yeah 
but carriers have two roles one is that they are themselves in danger of of 
serious health consequences the second is that they are actually transmitting 
to other people mm are there any questions about that mm okay so we can 
potentially use cure of carriage as a public health tool yep theoretically you 
could do the same thing with behaviour change if you could just say to carriers 
right don't transmit yeah or reduce viral load in those carriers to a to an 
extent you don't actually have to cure them if you could reduce viral loads to 
an extent that they were no longer infectious it would have the same effect but 
one of the key things for this is in terms of thinking about eradication 
eradication through vaccination is the time scale for it is very much related 
to duration of infectiousness 
and it took about two-hundred infection generations to eradicate smallpox yeah 
which is actually quite a small number when you think about it you start 
vaccinating against smallpox in a concerted effort to eradicate and from that 
that point there are only two-hundred further generations of transmission yeah 
but it's possible with smallpox because the duration of infectiousness is only 
measured in days or weeks carriers for hepatitis B can survive many decades so 
even if we said tomorrow right let's eradicate hepatitis B we're going to have 
to wait fifty or sixty years before those children who are carriers now yeah if 
they survive actually stopping carriers mm so two-hundred it may well be two-
hundred generations in terms of eradication but if we use clearance of carriage 
as a public health tool then we can reduce that time scale a lot and it 
actually makes eradication of hepatitis B a feasible proposition okay what i'm 
going to do now is i'm going to 
look at vaccination how does vaccination influence this picture yeah this is 
the same picture as i showed you before er except that rather than prevalence 
of infection up the vertical axis i've got proportion of carriers but you can 
see there's low endemicity high endemicity and this unstable boundary between 
them okay and then suppose we had two communities which i've labelled P and Q 
and these two communities are high endemicity and it would look very much as 
though in terms of field investigation anyway that they have the same 
endemicity yeah in actual fact they might have very different basic 
reproduction numbers for some reason but you know you wouldn't be actually be 
able to tell because everyone's infected because of this positive feedback so 
let's come along and let's vaccinate mm at fifty per cent so what i'm doing now 
is all i'm vaccinating fifty per cent of all children that are born and what 
that does 
is to ch-, shift the epidemi-, shift the equilibrium and it shifts them all to 
the right yeah which you shouldn't be surprised about because that means that 
now you need a for any particular er value you need a higher R-zero for the for 
the virus to survive but interestingly it shifts the low equilibrium faster in 
other words you can't use vaccination to move a population from high endemicity 
to low endemicity because this low equilibrium moves out of the way faster so 
you can't drop down from here to there yeah what you can do though is to 
eradicate infection so in this case vaccinating at fifty per cent this 
population up here with a basic reproduction number of two yeah i-, numbers of 
carriers will go down this population here the numbers of carriers will go down 
but they will only just cling on if i vaccinate at seventy per cent 
yeah then this population here with a basic reproduction number of one yeah 
we're now working on these lines would just drop down you will eradicate 
infection from that population but you won't eradicate it from this population 
because it's still got this high endemicity equilibrium supporting it mm does 
that make sense you're all too nervous about asking questions aren't you 
[laughter] okay so the effect of the immunization is that lower equilibra move 
faster than upper equilibria they're all shifting to the right so we can't use 
immunization to change the endemicity yeah but it enhances the bistability so 
it increases the usefulness of chemotherapy against carriers i haven't 
necessarily shown that result but the effect of of looking at these two 
together yeah there is a synergy in both curing carriage and vaccination yeah 
which enhances both and i shall 
skip that picture mm okay so bringing things together to a conclusion because 
of this positive feedback effect and the age-related probability of becoming a 
carrier hepatitis B transmission dynamics contain potentially complicated and 
very non-linear features and by non-linear i mean that if you double R-zero you 
don't just double the amount of infection yeah if i were to halve the amount of 
contact i won't just halve the size of the public health problem and the small 
changes in environmental behaviour can have large consequences because of this 
feedback loop magnifying the effect of any differences and that immigration and 
and carriage cure or carriage infectiousness removal or whichever term you like 
are really public health problems or interventions they are er features of 
hepatitis B that we can actually use to help reduce the size of the problem and 
potentially bring in the possibility of eradication it 
also raises the question of how general is this type of mechanism mm for 
example tuberculosis shows a very similar geographical trends yeah from north 
to south is there something in tuberculosis transmission which creates the same 
effect yeah in fact it turns out that you can get very similar results if you 
lo-, include the effect of dose response in particular the higher the dose of 
infection you get the more likely you're to be infected and the higher the dose 
of infection that you give yeah so you can have you have that kind of dose 
response you can end up with the same positive feedback that in one community 
you can have high doses giving rise to lots of people spreading viruses that 
give high doses to lots of virus and in another community you don't have that 
positive feedback you just have some low level infection low doses means that 
people are only infectious with low doses yeah so a kind of dose effect can 
produce the same split 
yeah and one of my one of the third years is currently doing their project on 
looking at that effect er in particular for tuberculosis to whether there is a 
high-low dose split the other question general question is whether there's a 
role for demographic change now there is something called a demographic 
transition which i'll talk more about in B-P-H-D next year er for those who are 
interested and demographic transition is essentially the move from developing 
country demography to developed country demography and developing countries are 
typified by having lots of children yeah er perhaps fifty per cent of people in 
sub-Saharan Africa are under the age of fifteen er fairly large households er 
population growing to the sti-, state where we have in the developed world 
where we have far fewer children the population is by and large much older and 
households tend to be somewhat smaller well if there's a positive role or a 
strong role for hepatitis B 
transmission within households yeah and particularly the fact that children 
play this critical role in terms of becoming carriers for hepatitis B then 
changing the demography changing household size and reducing the numbers of 
children in the population m-, reducing birth rates may well have an effect on 
the epidemiology so perhaps the the transition from high to low endemicity goes 
along with the demographic change that occurs from developing to developed 
countries mm so i would love to be able to go back two-hundred years in the U-K 
and take some sera and to look for hepatitis B because i think there is a 
strong possibility that two-hundred a hundred years ago we were a high 
endemicity country of hepatitis B but and we've lost that over the past hundred 
years through the dem-, through the demographic transition er but i'll i won't 
be able to do that so that is idle speculation