nm0283: okay as promised the lecture [0.5] er now is looking at hepatitis B [0.
3] virus there are no handouts for the this lecture but the first paper [0.4] 
in the list of references that i gave you [0.6] er [0.9] has actually got 
everything in that this lecture's going to talk about and more [0.4] so that 
can act as the notes for this lecture if you want something else to read [2.5] 
okay so what i'm going to do is to talk about hepatitis B virus [0.3] and i'm 
going to talk about [0.3] its epidemiology in the same way that i've talked 
about measles [0.4] and hopefully explain why it's different [2.6] this work 
was done jointly with er namex [0.4] who [0.7] i made the mistake one day as 
post-doc in the group [0.6] er made the mistake one day of showing him my 
payslip so he went off to work in [0.2] c-, computer industry [0.7] er [0.5] 
namex who now heads the [0.2] mathematical or the immuni-, er e-, epidemiology 
group [0.7] at er [0.3] er namex [0.6] er and and namex who's still around part 
of the department [2.3] 
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 [1.4] talk about its 
global prevalence [1.4] and then explain two particular epidemiological 
processes [0.6] that are u-, er in some ways unique [0.4] to [0.7] or one of 
them is unique to hepatitis B [0.5] and then show how that reduces equilibrium 
results er that are different from measles [0.4] and the effects that that can 
have in terms of trying to control [4.8] hepatitis B virus [1.5] causes acute 
disease in a minority of infections so about twenty per cent of people who are 
infected [0.5] actually develop [0.4] acute hepatitis [0.4] and a small very 
small proportion will actually die of it most people [0.4] go through an 
asymptomatic infectious stage which can last about six months but they don't 
know they've got hepatitis B [1.9] a proportion of individuals however will 
fail to clear that infection and will become carriers [0.9] and that's where 
the serious consequences of infection occur [0.5] because they 
induce a high turnover of liver cells so the the hepatitis is killing the liver 
cells [0.7] produces a high turnover [0.3] and so cirrhosis and primary hepatic 
cancer [0.5] or P-H-C [0.3] are actually consequences of long term carriage of 
hepatitis B [1.0] but people remain infectious as carriers for many decades 
many years [0.8] yeah so [0.5] there is a contrast between the acute phase 
that's months [0.9] and the carriage phase which is years [0.8] mm and remember 
duration of infectiousness [0.4] has an important role to play in epidemiology 
[2.5] hepatitis B virus is transmitted [1.0] by lots of different routes it's a 
classic small community virus [1.1] this virus has obviously been around in 
people for a long time and has evolved to live in small communities [1.5] so 
it's transmitted horizontally [0.6] by close contact although [0.4] many of the 
exact mechanisms are unknown it's it's [0.3] sort of close contact [0.6] body 
fluid transmission [0.8] from one person to another so sexual contact has an 
important role in [0.7] in developed countries [1.6] and also [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 [0.
7] er viral infection [0.5] er [0.4] but still in a medical setting [0.9] er [0.
3] infection is quite common so [0.7] one of the er [0.2] target groups for 
vaccination in the U-K are [0.2] health care workers so doctors and nurses are 
routinely vaccinated with hepatitis B [0.4] because they're likely to come in 
con-, contact with people who are infected more than [0.3] the rest of the 
population [0.9] and then finally there's a vertical transmission component [0.
8] from mother to child [4.0] the public health significance of hepatitis B [0.
4] is that it's a very common virus [0.5] so there are at least three-hundred-
million people who are carriers [0.9] and because of the age at which people 
get infected especially [0.3] er boys getting infected [0.3] who then develop 
[0.4] cancer and cirrhosis [0.4] in their sort of between twenty and forty 
years old [0.4] it has a s-, very significant economic impact because that's 
just when [0.7] 
people have got children and aged parents to support [1.4] so its economic 
impact is actually slightly bigger than its [0.6] health impact if you like [0.
5] so it does kill people but it kills a group [0.5] w-, who are economically 
productive [1.6] and the contrast [0.3] or or er or the flip side of that is 
the fact that we do have a very safe [0.4] cheap effective vaccines that you 
will have heard about already [0.5] er available for hepatitis B [0.5] so it is 
a potential [1.0] target in terms of control [0.5] er [0.5] economically 
important [0.2] health important [0.4] with a a good way of controlling it [4.
0] now [0.6] it turns out that the interesting thing about hepatitis B [0.4] is 
that it varies greatly in terms of its prevalence [1.4] so i'm going to 
contrast the Gambia [0.5] which is a small [1.1] elongated country in west 
Africa [0.7] er with the Republic of Ireland so talking about the results of 
this er [0.2] the study that i'd i mentioned er earlier this morning [1.5] so 
in the Gambia about eighty per cent of people [0.3] having been infected by the 
age ten it's a childhood viral 
infection [0.9] yeah much like rubella [0.5] or mumps [0.6] that children 
commonly get infected [0.4] and the vast majority will be infected before the 
age of ten [1.2] in the Republic of Ireland by contrast and and that goes for 
the U-K as well [0.6] only one-half of a per cent of the total population has 
ever been infected [1.7] so it's an enormous discrepancy [3.3] yeah so you end 
up with a c-, in essentially two [0.5] splits two paradigms if you like high 
endemicity [0.7] common childhood infection [0.5] low endemicity it's a rare [0.
4] principally adult infection [0.7] and predominantly known via risk factors 
so the people in the in the developed world [0.3] who get hepatitis B 
predominantly [0.3] have the risk factors of high numbers of sexual partners or 
intravenous drug users [0.8] yeah [1.2] in developing countries [0.3] high 
endemicity areas actually assigning the route of transmission [0.3] is much 
more difficult because it's it's [0.4] everyone's got it [0.4] and it's 
ubiquitous [2.3] so this figure illustrates this [0.3] high endemicity low 
endemicity split [0.8] that principally 
the developing world [0.6] so that is [0.3] by and large sub-Saharan Africa [0.
5] south-east Asia [0.8] er native s-, [0.2] native [0.4] Americans i guess in 
the Amazonian Basin [0.6] er [0.4] and Inuits [0.2] Eskimos [0.2] in northern 
[0.5] America [0.8] they these communities have very high endemicity [1.2] yeah 
the rest of the world [0.6] really doesn't [2.6] and the interesting thing is 
that there is no obvious explanation for this [0.8] you would like to think oh 
it's genetics [0.5] yeah it must be something to do with the hosts [0.4] 
however if you transfer people through immigration from a high endemicity area 
[0.3] to a low endemicity area [0.5] then after a generation [0.5] they've 
actually got low endemicity [0.2] infection so it's not not something to do 
with host genetics that makes people more susceptible [1.5] it's not something 
to do with the virus that makes it more transmissible [1.1] yeah [0.8] viruses 
from sub-Saharan Africa are continually being tr-, introduced into the U-K but 
we don't have [0.5] high endemicity [0.2] situation in the U-K [1.2] yeah [0.5] 
there are no specific behaviours which 
seem to be related [1.2] yeah [0.9] so the best current explanation [0.4] is 
the transmission is somehow higher in endemic areas [1.2] yeah [4.5] but it's a 
very hand-wavy sort of way [1.2] at least this explanation really relies on 
this basic reproduction number R-zero [1.3] yeah [2.2] that somehow there's a 
very small difference between the basic reproduction number in the U-K [0.4] 
it's very low [0.4] and the basic reproduction number in the Gambia it's a bit 
higher [0.9] for some unspecified reason [1.1] mm [1.8] so this is a picture 
that you've seen before [0.4] that somehow the U-K's basic reproduction number 
is way down here [0.8] yeah [0.8] just enough [0.6] to have one-half of one per 
cent of people infected [1.1] yeah [0.4] and that the Gambia [0.4] is up here 
somewhere [1.5] but there's no explanation [0.5] well no other explanation as 
to why [0.3] there should be that difference [1.6] yeah [2.6] are there any 
questions [7.4] okay so it varies greatly between countries between different 
communities [0.9] mm [0.3] however [0.5] if you actually go to the country [0.
6] it varies greatly within the country as well [2.0] so if you 
go to two for example villages in Alaska [0.9] same people [0.8] genetically 
speaking [0.6] same behaviour same culture [0.6] then the the prevalence of 
carriage can vary between zero and twenty per cent [1.6] so any explanation 
that you have [0.4] about [0.4] this variability [0.3] has to include [0.2] a 
local component [0.3] in fact the local component is almost bigger than the [0.
5] national one international one [1.6] yeah [0.7] so in fact you would expect 
very little difference in basic reproduction numbers and basic transmission [0.
4] between neighbouring villages [0.7] so the explanation about oh it's R-zero 
it's contact it's behaviour [0.2] it's genetics [0.4] completely falls down [0.
7] mm [5.9] okay well why is that interesting well it's scientifically 
interesting [0.7] but it's also interesting in terms of control [0.9] what are 
we going to do about it [1.2] at the moment barring some [0.3] drugs which are 
still under trial but at the moment immunization is the only public health 
measure that we have [0.7] yeah [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 [0.5] let's vaccinate everybody [1.1] yeah 
[0.9] and the indication is that you don't need a very high coverage [0.5] to 
actually control or eradicate the infection [0.5] yeah i-, vaccination is quite 
clearly [0.5] the best option for control [1.6] but there is considerable 
discussion and i put discussion in inverted commas because it's actually 
downright argument [0.6] considerable discussion over whether or not it's 
appropriate for something like the U-K [0.9] low endemicity countries [0.7] to 
vaccinate [1.3] because only one person in two-hundred is actually going to get 
hepatitis B [0.4] so you're going to be vaccinating a hundred-and-ninety-nine 
children [0.6] for no reason whatsoever [1.5] course what you'd like to do is 
to walk into a classroom at the age of [0.2] children at the age of five and 
say right [0.3] all those of you who are going to [0.2] use intravenous drugs 
when you're older [0.4] [laughter] and have more than 
five sexual partners a year could you please put your hand up and we'll 
vaccinate you but [0.7] that doesn't happen [0.8] so you'd have to vaccinate 
all children [0.9] so there is a cost issue [1.5] in terms of you're actually 
wasting a hundred-and-ninety-nine [0.4] vaccine cases wasting [0.9] in inverted 
commas in effect wasting them [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 [0.6] ever get a risk for having [0.7] mm [1.5] so [1.0] if we 
could actually find a reason for this endemicity change this this low-high 
endemicity split [0.5] it might help [0.4] designing control programmes so at 
the moment in the U-K we have a targeted programme [0.7] that is that we vac-, 
offer vaccination to people who have specific risk factors [0.5] of multiple 
sexual partners intravenous drug use [0.8] er but of course then you have to 
wait for them to have those risk factors before you can vaccinate them [3.0] so 
[0.8] hepatitis B immunization policy this is [1.3] er [0.6] a good reason 
for buying into Microsoft [0.2] computer products [0.6] the Bill and Melinda 
Gates Foundation [0.4] gives a vast amount of money more money [0.2] than you 
can possibly imagine [0.5] to h-, to help control [0.5] vaccine preventable 
diseases like hepatitis B [0.7] so this [0.2] picture is well out of date now 
it's [0.3] this is er from three years ago [0.4] most of the world is coloured 
blue most of the world has now got routine immunization [0.3] and a lot of it 
is being paid for [0.7] by Bill and Melinda Gates [0.6] the few countries that 
are refusing to adopt [0.2] vaccination include the U-K [0.4] Scandinavia [0.4] 
and the Netherlands [0.7] principally because of this reason of [0.9] of [0.2] 
not wanting to vaccinate children when they don't need to be [0.8] but most of 
the rest of the world has got this universal vaccination of children [2.3] so 
[1.2] that's a kind of introduction [1.3] so i'm now going to provide you with 
a better explanation for this variation in prevalence between communities [1.4] 
yeah [4.6] assesses the interplay between two separate epidemiological 
processes [0.9] wo-, first is that the proportion 
of people who develop carriage is highly age-dependent [1.0] yeah [2.6] if you 
are young [0.5] and by that i mean [0.4] the younger you are the say months old 
[0.5] then your chances of becoming a carrier and infected than if you're an 
adult [2.5] the second is that the average age of infection decreases [0.5] the 
more infection there is and i ta-, touched on this earlier today that the more 
common the virus is in the population [0.5] the earlier people will be when 
they first get infected [1.4] yeah [0.8] and because of the differing time 
scales [0.7] in terms of acute infection versus carriage [0.2] months versus 
decades [0.5] carriers [0.6] are more important in terms of transmission [0.8] 
that a carrier will infect approximately five times more people [0.4] than an 
acute case [0.4] because of that length of time over which they're infectious 
[2.0] so the average age of infection will go down [0.6] the more carriers 
there are [1.1] yeah [2.4] does that make sense [5.3] okay just to give you 
some data to illustrate these 
points [0.6] this shows [0.3] picture shows the probability of carriage [1.6] 
on the vertical axis against age of infection in years on the horizontal axis 
[0.8] each of the red crosses represents a [0.2] single study [0.7] where 
people looked at infection in an age in a group of of people [0.5] and saw what 
percentage of them became carriers [1.2] er and the circle around [0.9] er each 
of these studies represents the size of the study so this study here [0.4] had 
about two-hundred people in it [0.3] and this one here will have had v-, er [0.
3] you know far fewer people in it [2.2] but you can see there is a clear 
relationship here whereabouts up here [0.5] if somebody is infected at birth [0.
3] by their mother [1.1] then they have about a ninety per cent chance of 
becoming a carrier [2.9] and that percentage that risk or probability drops 
quite dramatically [0.5] so that by the time you get to the age of ten [0.5] 
you're talking about five per cent [0.7] oh sorry [0.7] fifteen per cent [0.9] 
yeah [0.6] and it's about five per cent for adults overall [0.8] so there's a 
very strong age relationship [1.3] yeah [4.2] 
this is the relationship between the rate of infection [0.9] the amount of 
virus that's there in principally carriers [0.3] and the age at infection [1.3] 
so the more [0.2] infection there is [0.2] yeah the [0.4] if you th-, can think 
of the s-, numbers of carriers going up this axis [0.6] the lower the average 
age at infection will be [1.8] yeah [1.9] so these two things [0.3] interact [0.
3] ignore the equation [2.5] so the more carriers you have [0.8] the lower the 
average age at infection [1.1] so the more carriers you will create [1.3] which 
will give you more carriers [1.1] which will mean that the average age at 
infection is lower so there's a positive feedback loop [0.9] the lower the 
average age at infection [0.2] the higher the numbers of carriers you create [0.
5] and so the higher the rate of infection and so the lower the average age at 
infection [0.2] yeah [4.8] can everyone see that there's this positive feedback 
[1.1] created in hepatitis B [0.4] by the fact that the probability of becoming 
a carrier [1.5] is higher the younger you are 
when you're infected [3.9] yeah [0.4] any [3.0] confusion [0.6] no [3.4] skip 
that one [0.5] skip that one [2.1] okay so this positive feedback [0.2] creates 
[1.1] a difference a change in this [2.1] equilibrium diagram that i showed you 
earlier remember in the [0.4] equilibrium diagram i showed you before [0.7] has 
the basic reproduction number determining [0.5] a threshold for when infection 
occu-, can occur [0.4] or when it can be sustained in a population [1.2] and 
here you see this threshold down here [0.8] yeah [0.6] so for relatively low 
values of the basic reproduction number and low values [0.6] or n-, small 
numbers of infected individuals [0.7] you essentially have a U-K situation so 
this black line represents [0.4] a developed country a U-K situation [0.8] 
where the rate of infection is very low [0.2] not many people have er hepatitis 
B [1.1] that means the average age at infection is quite high [0.5] because you 
have to live quite a long time 
before you meet somebody who's got hepatitis B [0.8] which means the chances of 
becoming a carrier are quite small [1.2] yeah [0.3] so it's essentially an 
adult infection [3.5] this equilibrium up here [1.4] is the high endemicity 
paradigm [1.6] everybody has hepatitis B which means that all children get 
hepatitis B [0.3] which means that they become carriers [0.4] and it's this 
positive feedback loop [1.2] yeah [2.3] so you have two endemic states a low 
one and a high one [1.4] and what's interesting [0.9] in some ways is that is 
that for regions of the basic reproduction number [1.2] these two endemic 
states can coexist [1.0] yeah [1.4] so [1.4] what you have is these arrows 
representing [0.2] how the popsulation will change [0.3] in terms of [0.4] 
endemicity [0.6] yeah when it's away from its equilibrium [1.9] so you have two 
endemic states separated by this [0.3] red line which is an unstable boundary 
[0.8] so if you're down here in the U-K [1.0] and for some reason you increase 
the amount of hepatitis B [0.4] to go above this unstable 
boundary [1.9] then you cross over into a high endemicity regime [0.9] you've 
got enough infection [0.4] to enable children to become infected to become 
carriers [0.3] to start off this positive feedback loop [0.4] so the amount of 
infection will then increase up to high endemicity [1.5] yeah [4.4] so these 
two endemic states come about because of this high positive feedback loop [2.3] 
and they can coexist [0.7] so there need be no reason why the Gambia is 
different from the U-K [1.1] other than the fact that the Gambia has a high 
prevalence [0.9] and the U-K has a low prevalence [3.4] yeah [1.8] somehow the 
Gambia started high and stay there [0.5] and somehow we've ended up down here 
[0.6] but there's there need be no other explanation [1.4] yeah [2.8] and i'm 
going to talk more about that [0.5] or i'm going to try and explain that more 
in a minute [0.9] the other feature from this picture [0.9] is the fact that [0.
6] you can have viral per-, [0.3] persistence in a population [0.8] in a p-, [0.
2] in a population where it couldn't invade [0.9] so where the basic 
reproduction 
number is less than one [1.9] yeah down here [1.7] if you introduce some 
infection [1.3] basic reproduction number is less than one [0.7] the change of 
transmission won't occur [1.6] but if you introduce enough infection [1.7] you 
actually cross into this high endemicity state [1.6] so in ecological terms if 
you like [0.3] what hepatitis B is doing is is [0.4] changing the host 
population [0.6] yeah it's it's making everyone t-, be a carrier so that the be-
, can sustain itself [0.3] in a population which it couldn't invade [1.9] mm [5.
1] are there any questions [7.8] okay so this is different [0.5] because of 
this positive feedback means infection can exist in a population [0.3] that it 
couldn't invade into [0.9] yeah and there's more complicated relationship 
between R-zero and seroprevalence in other words [0.6] the methods that i 
talked about earlier for looking at age serological profiles just wouldn't work 
[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 [0.4] but in fact R-
zero could be less than 
one [1.1] in the Gambia [0.9] mm [1.5] and it produces these two stable 
possibilities high and low endemicity [0.4] which are both self-sustaining [0.
3] both stable [0.9] and which one you're at depends on where you start from [4.
3] now i have to mention these but i'm not going to go into any detail [0.5] 
this is all controlled by two important parameters [0.8] one of which is the 
relative infectiousness of carriers [0.8] so although carriers are infectious 
for a longer period of time than acute cases [0.4] they are less infectious [1.
3] yeah [3.0] the other [0.3] parameter [0.7] is something i've called F [0.5] 
which is the proportion of infected adults that become carriers [0.7] yeah [0.
6] now the reason i highlight these two parameters is because there isn't 
actually much data on these two [1.7] yeah [1.0] what data there is and i've 
showed it to you suggests the proportion of infected adults [0.5] who become 
carriers is about five per cent but [0.4] you know it could be [0.8] as high as 
eight or it could be as low as three [2.3] now whether or not these [1.0] occur 
[1.2] yeah and this is 
this is looking at the F and alpha in this figure here [0.6] whether or not 
this pattern occurs of this [0.7] multiple equilibria [1.3] depends very much 
on these two parameters [1.2] so in this picture here [0.5] i am [0.6] varying 
this alpha and this F so the relative infectiousness of carriers [0.4] and the 
proportion of adults who become carriers [0.7] so the solid black line [0.8] is 
the one that i showed you earlier that's just the the basic relationship 
between R-zero and seroprevalence [0.6] this is the one i showed before [0.5] 
yeah and these other [0.3] lines are varying these parameters for which we have 
little information [1.9] okay [4.4] so another r-, result from this is that [0.
4] it's not just the fact that you can get these multiple endemicities but the 
fact is that they are very sensitive [0.7] to the parameters that you choose [1.
3] so it might be that the Gambia [0.4] is different from the U-K [0.5] perhaps 
in terms of diet [0.8] which somehow means that adults [0.3] are just [0.3] a 
little more likely to become carriers than [0.8] than people who don't have 
that 
diet in the U-K [1.0] and the difference is so small [0.3] that you can't 
measure it [1.2] without doing large studies [1.0] but in fact [0.5] it has a 
big impact on the epidemiology [1.5] yeah [1.7] so it's a it's a phenomenon 
called criticality the the the s-, dynamic situation is critically dependent [0.
5] on some values of the parameters [2.6] and actually measuring those 
parameters in the field is very difficult [3.5] okay what i'm going to do now 
is to kind of illustrate [1.7] potentially how we could explain this endemicity 
[2.1] so this [0.4] figure here shows what happens [0.5] if you take this 
system [0.8] over a period of this case five-thousand years [0.6] because 
hepatitis B carriage is is quite persistent [0.3] it means that [0.5] the time 
scales over which hepatitis B changes are quite long [1.1] yeah [0.7] but let's 
take [0.2] so this just running over five-thousand years [0.8] and i start off 
at some level of infection [1.0] and there where each of the arrows occurs 
vertical arrows what i'm doing is i'm [0.2] reducing the basic reproduction 
number [1.6] okay [4.9] let me go [0.7] back [3.3] 
i'm actually starting on here [0.3] yeah [0.2] so i'm starting at a value here 
[0.8] yeah [0.4] and then i'm reducing the basic reproduction number to allow 
the the [0.4] the system to go to the next equilbrium [1.6] yeah [0.2] so i'm 
going here down to the next equilibrium then i'm reducing the basic 
reproduction number again [0.4] going down to the next equilibrium [0.4] and 
reducing the basic reproduction number going to the next one [0.3] and 
eventually it goes extinct [1.1] yeah [0.4] so i'm essentially moving down that 
lower curve [1.5] yeah [0.2] does that make sense [7.4] if i start just above 
[0.2] that unstable equilibrium that red dotted curve in the equilibrium 
diagram [0.7] i go up to the high equilibrium [1.5] yeah [0.6] so the 
difference in the starting point [0.3] between those two [0.5] is as small as 
you like [0.6] yeah [2.4] above it we go up below it you go down [1.1] and here 
i reduce the basic reproduction number again [0.7] and this 
point here [0.2] between these two [0.3] reductions of the basic reproduction 
number [0.7] is something [0.3] called a catastrophe [0.5] yeah the technical 
term for it [0.8] where a small change in a parameter produces a [0.3] a very 
big result [0.4] and essentially what's happening is i'm falling off [0.4] the 
end of the high endemicity and dropping down to the low endemicity [1.3] yeah 
[1.3] so in these [1.2] curves here [0.3] if i change the basic reproduction 
number [0.3] so that i just drop off the end [0.8] then i get a very dramatic 
change [0.4] in the [1.3] proportion positive [1.1] for a very small change in 
the parameter [1.6] yeah [3.0] so does that make sense [2.4] remember not to go 
backwards again [1.9] i've never done it with loudspeakers on so [2.0] any 
questions [1.7] 
sf0284: are those 
nm0283: yeah 
sf0284: two parameters defined in the journal [0.2] or are they just 
nm0283: yes 
sf0284: just like [0.4] they are [0.2] 
nm0283: they are 
defined yeah [6.3] so a very small change in the parameters [0.4] or the 
starting point [0.3] can lead to a large [0.3] changes in outcomes [0.7] yeah 
[1.9] and these changes these these [0.4] differences [1.1] can be so small 
that in fact they're undetectable [0.5] in most field studies [1.7] so 
additional heterogeneity [0.5] is potentially going to come from the fact [0.5] 
that if you have populations that are in transition [0.5] between one state and 
another [1.0] yeah they're moving slowly [0.7] they are in transition [0.6] 
then [0.2] you'll get additional heterogeneity [0.4] so one thing i didn't 
point out f-, was that [0.5] although we have high and low endemicity states [0.
4] sub-Saharan Africa and the U-K [0.6] much of southern Europe and north 
Africa [0.3] are in-, have intermediate [0.3] epidemiology [1.6] so this would 
suggest that in between [0.7] yeah intermediate [0.3] endemicity [0.4] there 
are actually countries on their way [0.2] from high to low potentially [2.2] 
yeah [1.3] if you look at a country like Tunisia [0.3] you can actually see a 
cl-, almost a cline 
of hepatitis B [0.3] from south to north [0.8] yeah that that you're actually 
seeing hepatitis B [1.3] going down as you go north through the country [1.5] 
mm [0.5] so there's a sort of geographical variation which is perhaps due to [1.
4] this this [0.6] transition from high to low [6.6] okay so is everybody happy 
about that explanation for different epidemiologies [3.4] okay what i want to 
do now [0.7] is to talk about [0.4] the consequences of this [0.5] in terms of 
public health [2.3] and the first is the fact that you're going to potentially 
have [2.2] different epidemiological [1.2] scenarios high or low endemicity [0.
5] in the same country [0.6] yeah if if this is right there is no reason why we 
shouldn't have high endemicity in the U-K [1.3] yeah [0.3] the only reason we 
don't have high endemicity is because we don't have high endemicity [1.4] but 
if we infected lots of children tomorrow [0.9] and they became carriers [0.6] 
that would create the situation where the other children would become infected 
and they would become carriers [0.4] and so on [0.5] yeah we'd move to high 
endemicity [1.6] 
so we can illustrate that by looking at [1.1] the effect of [1.3] introducing 
carriers into a population [1.1] yeah [1.1] so we start off at low endemicity 
[1.6] introduce some carriers [2.2] if we introduce [2.0] enough [0.6] to make 
it high but not to cross over the boundary we get a little epidemic [0.2] of 
infection [0.4] but it settles back down to the low equilibrium [1.0] mm [1.6] 
but if we cross the boundary [0.7] and introduce enough carriers [0.5] then we 
create this positive feedback [0.3] which results in a g-, moving up to high 
endemicity [1.7] mm [1.3] so we're just crossing over that red dotted line on 
the equilibrium boundary [1.5] so this potentially has important consequences 
[0.5] when thinking about for example immigration [1.4] and in fact bringing 
hepatitis B carriers [0.4] into a low endemicity country [0.3] might well 
create the possibility [0.3] of moving to a high endemicity [1.6] yeah [0.6] or 
for example failure of blood tranfusion services to actually detect hepatitis B 
[0.7] if we created lots of carriers [0.6] then we might move into a situation 
of high endemicity [2.9] so there is this 
potential [2.1] of moving to high endemicity [1.5] now [0.4] whenever you talk 
about immigration or mention that word it [0.2] it prod-, usually produces a 
kind of [0.6] er [0.4] bistable response in itself [1.3] 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 
[0.9] which actually turns this on its head and says well [0.4] in fact the 
majority of carriers in the U-K [0.4] do actually come from overseas they were 
infected [1.2] overseas so they're they've emigrated to the U-K [0.3] they've 
brought their hepatitis B carriage with them [4.0] so in fact the most cost-
effective policy [0.5] for the Department of Health [0.4] when it trying to 
deal with hepatitis B carriage in the U-K [1.2] is to vaccinate people [0.6] in 
the countries [0.8] where immigration starts from [2.1] yeah [3.4] in terms of 
vaccination we shouldn't be vaccinating people in the U-K we should be 
vaccinating people outside [0.4] because that's where our hepatitis B comes 
from [1.4] so it turns round a [0.5] a sort of an anti-immigration [1.3] 
argument [0.4] into one that's much more positive in terms of [0.6] sharing 
health care globally [0.9] mm [8.1] 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 [0.3] a very [0.3] important idea [0.6] er that sooner or later everyone's 
going to catch on to [0.8] er that [0.6] vaccination [0.4] overseas in terms of 
of increasing global travel incleepa-, increasing globalization [0.3] is going 
to be the most cost-effective way [0.3] in which we control infection in this 
country [5.0] okay the f-, [0.6] the other [0.8] consequence of this [1.3] dual 
end-, er high-low endemicity [0.3] dichotomy [0.4] is the fact that if you have 
a drug that could cure carriage [1.4] yeah you could use it as a public health 
tool [1.1] now at the moment such a drug doesn't exist there are drugs which 
you can use to suppress [0.4] viral replication [0.4] if for example you're 
going to do some sort of er [0.3] er blood er liver transplant [0.7] er [0.3] 
but resistance arises quite quickly to them [0.3] so there isn't anything yet 
which we [0.2] we have [0.5] use 
al-, you can use although there are [0.2] s-, many things [0.3] in the pipeline 
[0.5] but let's suppose that we had something [0.9] so we can actually start at 
high endemicity [0.5] and we could reduce the numbers of carriers we could go 
out into the community and we could say right [0.8] we're going to cure 
carriage [0.9] everyone we can find [1.2] if we remove that level of carriage 
from the population [0.6] yeah to some degree [0.7] it means that children 
would no longer potentially become infected as ch-, er become infected [0.5] 
which means that they wouldn't create carriers [0.3] so you would break this 
positive feedback [1.2] yeah [0.4] so again you get this bistability [0.4] 
effect that if you cross this threshold [0.7] you reduce the level of carriage 
enough [0.5] you can actually switch from high to low endemicity [3.7] yeah [5.
7] now this is [0.9] again quite novel because people think in terms of curing 
carriage in terms of curing individuals [1.0] preventing people getting 
cirrhosis and hepatic [0.6] and primary hepatic cancer [0.5] not [0.5] in terms 
of a public health tool [1.7] yeah [0.8] but carriers have two roles one is 
that they are themselves [0.4] in danger of of serious health consequences [0.
5] the second is that they are actually transmitting to other people [1.4] mm 
[5.3] are there any questions about that [1.8] mm [3.3] okay so we can 
potentially use [0.5] cure of carriage as a public health tool [1.2] yep [0.8] 
theoretically you could do the same thing with behaviour change if you could 
just say to carriers right don't transmit [0.7] yeah [0.2] or reduce viral load 
[0.2] in those carriers [0.2] to a to an extent you don't actually have to cure 
them [0.6] if you could reduce viral loads to an extent that they were no 
longer infectious it would have the same effect [1.6] but one of the key things 
[0.6] for this is in terms of thinking about eradication [1.9] eradication 
through vaccination [0.9] is [0.5] the time scale for it is very much related 
to duration of infectiousness [1.9] 
and it took about two-hundred [0.6] infection generations to eradicate smallpox 
[1.0] yeah [0.5] which is actually quite a small number when you think about it 
[0.4] you start vaccinating against smallpox in a concerted effort to eradicate 
[1.4] and from that [0.3] that point there are only two-hundred further 
generations of transmission [1.4] yeah [1.1] but it's possible with smallpox 
because the duration of infectiousness [0.4] is only measured in days or weeks 
[2.7] carriers for hepatitis B can survive many decades [0.8] so even if we 
said tomorrow right let's eradicate hepatitis B [0.6] we're going to have to 
wait [0.2] fifty or sixty years [0.5] before those children who are [0.3] 
carriers now [1.0] yeah [0.2] if they survive [0.7] actually [1.0] stopping 
carriers [1.2] mm [0.4] so two-hundred it may well be two-hundred generations 
[0.4] in terms of eradication but if we use [0.6] clearance of carriage as a 
public health tool [1.8] then we can reduce that time scale a lot [0.3] and it 
actually makes eradication of hepatitis B [0.3] a feasible proposition [6.7] 
okay [0.2] what i'm going to do now is i'm going to 
look at vaccination [0.7] how does vaccination influence [0.6] this picture [0.
8] yeah [0.6] this is the same picture as i showed you before [0.4] er except 
that rather than [0.8] prevalence of infection up the vertical axis i've got 
proportion of carriers [0.5] but you can see there's low endemicity high 
endemicity and this unstable boundary between them [1.5] okay [2.6] and then 
suppose we had two communities which i've labelled P and Q [2.5] and these two 
communities are high endemicity [1.1] and it would look very much as though [0.
5] in terms of field investigation anyway that they have the same endemicity [1.
3] yeah in actual fact they might have very different basic reproduction 
numbers for some reason [0.6] but [0.5] you know you wouldn't be actually be 
able to tell because everyone's infected because of this positive feedback [1.
5] so let's come along and let's vaccinate [0.5] mm [2.5] at fifty per cent so 
what i'm doing now is all i'm vaccinating fifty per cent of all children that 
are born [1.1] and what that does [1.3] 
is to ch-, shift the epidemi-, shift the equilibrium [1.3] and it shifts them 
all to the right [0.9] yeah [1.5] which you shouldn't be surprised about [0.7] 
because that means that [0.4] now you need a [0.4] for any particular [0.5] er 
value you need a higher R-zero for the for the virus to survive [1.6] but 
interestingly [0.4] it shifts the low equilibrium [0.2] faster [1.6] in other 
words you can't use vaccination [0.5] to move a population from high endemicity 
to low endemicity [3.5] because this low equilibrium moves out of the way 
faster [1.2] so you can't drop down [0.4] from here [0.5] to there [0.9] yeah 
[2.4] what you can do though is to eradicate infection [1.0] so in this case 
vaccinating at fifty per cent [0.4] this population up here with a basic 
reproduction number of two [0.5] yeah i-, [0.4] numbers of carriers will go 
down [1.0] this population here [0.2] the numbers of carriers [0.3] will go 
down but they will only just cling on [0.9] if i vaccinate at seventy per cent 
[1.4] 
yeah [0.3] then this population here with a basic reproduction number of one [0.
4] yeah [1.7] we're now working on these lines [0.7] would just [0.5] drop down 
[0.7] you will eradicate infection from that population [0.4] but you won't 
eradicate it from this population because it's still got this [0.4] high 
endemicity equilibrium supporting it [2.2] mm [4.1] does that make sense [5.4] 
you're all too nervous about asking questions aren't you [5.3] [laughter] okay 
so the effect of the immunization is that lower equilibra move faster than 
upper equilibria [0.2] they're all shifting to the right [0.6] so we can't use 
immunization [0.6] to change the endemicity [1.2] yeah [1.7] but it enhances 
the bistability [0.4] so it increases the usefulness [0.5] of chemotherapy 
against carriers [5.1] i haven't [1.6] necessarily shown that result [0.3] but 
the effect of of looking at these two together [0.7] yeah there is a synergy [0.
2] in both curing carriage and vaccination [0.8] yeah which enhances both [4.9] 
and i shall 
skip [1.4] that picture [1.2] mm [11.2] okay so [1.4] bringing things together 
to a conclusion [3.0] because of this [0.6] positive feedback effect and the 
age-related probability of becoming a carrier [0.8] hepatitis B [0.2] 
transmission dynamics contain [0.7] potentially complicated [0.3] and very non-
linear features and by non-linear [0.4] i mean that if you double R-zero you 
don't just double the amount of infection [0.8] yeah [0.6] if i were to halve 
[0.5] the amount of contact i won't just halve the size of the public health 
problem [1.3] and the small changes in environmental behaviour [0.4] can have 
large consequences [0.5] because of this feedback loop magnifying the effect of 
any differences [1.9] and that immigration and and [0.2] carriage cure or 
carriage infectiousness removal or [0.5] whichever term you like [1.2] are 
really public health problems or interventions [0.7] they are [0.7] er features 
of hepatitis B that we can actually use [0.7] to help reduce the size of the 
problem [0.7] and [0.3] potentially bring in the possibility of eradication [8.
0] it 
also raises the question of how [0.6] general is this type of mechanism [1.3] 
mm [1.0] for example tuberculosis shows a very similar [0.4] geographical 
trends [1.2] yeah from north to south [1.5] is there something in [0.5] 
tuberculosis transmission [0.6] which [0.5] creates the same effect [1.2] yeah 
[3.1] in fact it turns out that you can get very similar results [0.6] if you 
lo-, include the effect of dose response [0.3] in particular the higher the 
dose of infection you get [0.6] the more likely you're to be infected [0.7] and 
the higher the [0.3] dose of infection that you give [2.3] yeah so you can have 
you have that kind of dose response you can end up with the same positive 
feedback [0.8] that in one community you can have [0.2] high doses giving rise 
to lots of people spreading viruses that give high doses [0.3] to lots of virus 
[0.8] and in another community you don't have that positive feedback you just 
have some low level infection low doses [0.5] means that people are only 
infectious with low doses [0.7] yeah [1.1] so a kind of dose effect [0.4] can 
produce the same split [1.5] 
yeah [2.8] and one of my one of the third years is currently doing their 
project on [0.7] looking at that effect [0.6] er in particular for tuberculosis 
to whether there is a high-low dose split [2.3] the other question general 
question is whether there's a role for demographic change [1.6] now there is 
something called a demographic transition which i'll talk more about [0.3] in 
[0.4] B-P-H-D next year [0.6] er for those who are interested [1.1] and 
demographic transition [0.2] is essentially the move from developing [0.6] 
country demography [0.5] to developed country demography [0.7] and developing 
countries are typified by having [0.6] lots of children [0.4] yeah er [0.5] 
perhaps fifty per cent of people in sub-Saharan Africa are under the age of 
fifteen [0.8] er [0.4] fairly large households [0.6] er [0.2] population 
growing [0.9] 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 [0.4] and 
households tend to be somewhat smaller [1.9] well if there's a positive role [0.
2] or a strong role for hepatitis B 
transmission within households [1.1] yeah and particularly the fact that 
children play this critical role in terms of becoming carriers for hepatitis B 
[0.9] then changing the demography [0.3] changing household size [0.4] and 
reducing the numbers of children in the population [0.4] m-, reducing birth 
rates [0.3] may well have an effect on the epidemiology [1.7] so perhaps the 
the transition from high to low endemicity [0.4] goes along with the 
demographic change [0.7] that occurs from developing to developed countries [1.
1] mm [1.7] so i would love to be able to go back two-hundred years in the U-K 
[0.3] and take some sera [0.4] and to look for hepatitis B because [0.8] i 
think there is a strong possibility that [0.4] two-hundred a hundred years ago 
[0.5] we were a high endemicity country of hepatitis B [1.8] but [0.3] and 
we've lost that over the past [0.3] hundred years through the dem-, through the 
demographic transition [0.7] er but i'll i won't be able to do that so that is 
idle speculation