Viral Hepatitides - Game Over? with Joseph Lim

Transcript

• 00:06I think, yeah, you're muted.
• 00:10Sorry about that.
• 00:11Our next speaker is Doctor Joseph Lim,
• 00:14who's professor of Medicine,
• 00:16Director of Clinical Hepatology.
• 00:18Within the section of digestive
• 00:19diseases and the Vice chief of
• 00:22the section of digestive diseases
• 00:24here at Yale and his optimistic
• 00:26topic is viral hepatitis game over.
• 00:31Joseph.
• 00:33Read it, thank you so much for
• 00:35the opportunity to be here.
• 00:36Special congratulations to Michael and
• 00:39Mario for this really amazing program
• 00:42today to celebrate 75 years of your liver,
• 00:45I've been tasked with a topic of viral
• 00:48hepatitis game over question mark
• 00:49and I think that's going to be very
• 00:52important because my hypothesis is that
• 00:54it's going to be a very challenging
• 00:56in fact to achieve this goal of
• 00:59elimination of both acute and chronic
• 01:01viral hepatitis in the short term.
• 01:04And as we will highlight furthermore,
• 01:06that The Who and the US Department Health
• 01:09Services have actually articulated
• 01:10specific goals for vehicles limination
• 01:13in the United States and globally.
• 01:15So a very briefly what to do is go through
• 01:19the abilities that will be discussed today.
• 01:23Briefly, hepatitis ABCD&E many of you
• 01:27are very familiar with the concept
• 01:29that whereas chronic hepatitis BC&D
• 01:31are largely bloodborne or body fluid.
• 01:35Mediated transmission with a chronic form.
• 01:38Acute hepatitis. I'm sorry.
• 01:39Acute hepatitis A and hepatitis E
• 01:42generally are transmitted through
• 01:44fecal oral transmission and are
• 01:46predominantly in acute form with very,
• 01:49very rare chronic form,
• 01:50at least in the case of hepatitis E,
• 01:53so peptides a very briefly a question.
• 01:56I'm raised opposed to there is.
• 01:59Can we limit the hepatitis A hepatitis
• 02:01A is an RNA virus that presents.
• 02:04In the form of acute hepatitis with a
• 02:07very low rate of fulminant hepatic failure,
• 02:10the global incidence of of acute
• 02:12HIV is proxy 1.4 million cases per
• 02:15year in the United States,
• 02:17or sorry globally,
• 02:18but the incidence in United
• 02:19States has been rising actually
• 02:22quite substantially since 2016.
• 02:23In the figure on the right you
• 02:25can see here that there has been a
• 02:27significant rise in both reported
• 02:29and estimated infections such that
• 02:31by 2019 the estimated number of
• 02:33infections approximately 37 to 38.
• 02:351000 within that year,
• 02:37and we believe that there are very
• 02:39specific at risk groups of which
• 02:42this is particularly common,
• 02:43but the risk factors that
• 02:45benefited our injection drug use,
• 02:46sexual contact country,
• 02:48and the MSM population, household contacts,
• 02:51international travel.
• 02:52And although this is not described
• 02:54in the risk factor analysis,
• 02:56we know that these are overrepresented
• 02:58in the homeless populations which
• 03:00for which we have identified
• 03:02specific outbreaks across multiple
• 03:04urban areas with the United States.
• 03:05Now state report outbreaks was begun
• 03:08to be collected by the CDC in 2016,
• 03:10and so over the last five to six years.
• 03:13Specifically in the context outbreaks,
• 03:15they're over 43,000 cases in over
• 03:1926,000 hospitalizations and 423 deaths
• 03:22attributable to hepatitis A infection,
• 03:24and so,
• 03:25whereas we historically have believed
• 03:26this to be associated with very
• 03:28low rates of flow and liver failure
• 03:30of zero point,
• 03:301% more recent data here in the
• 03:33United States suggest case fatality
• 03:35rates approaching 1.0.
• 03:36Percent,
• 03:36and this is been concentrated again
• 03:39in very specific populations,
• 03:41particularly in those with
• 03:43immunocompromised or chronic liver disease.
• 03:45Do we have a vaccine?
• 03:46Hepatitis A yes, this is viewed as a vaccine.
• 03:49Preventable infection in
• 03:50the form of havrix or vecta,
• 03:52and unfortunately we have clear
• 03:55documentation that vaccination rates
• 03:57in the United States and endemic
• 04:00regions remain startling low,
• 04:02and therefore there remains much
• 04:03work that needs to be done.
• 04:04If we're going to achieve elimination of.
• 04:06It's a incidence in the
• 04:09United States and worldwide.
• 04:11There is one treatment and specific
• 04:13context of those who are at high
• 04:15risk for morbidity and mortality
• 04:17and form of immune globulin.
• 04:20Hepatitis B briefly is a DNA virus for
• 04:22which we have both acute and chronic
• 04:24forms of the global burden is substantial.
• 04:27It is estimated that over 2 billion
• 04:29persons have been infected acutely
• 04:31and that the chronic form of
• 04:33hepatitis B is currently present
• 04:35in 257 to 292,000,000 person.
• 04:37Globally,
• 04:38our research group and Clarion with Stanford,
• 04:40with many nuyen and Rakim have
• 04:43demonstrated evidence that the
• 04:45updated US burden is approximately
• 04:471.6 million persons globally.
• 04:50This amounts to approximately
• 04:51120,000 deaths per year.
• 04:53On top of that we have new infections
• 04:55numbering in approximately
• 04:561.5 million persons per year.
• 04:58We recognize there's substantial
• 05:00under diagnosis of hepatitis B and
• 05:03unfortunately our current guidelines
• 05:05by the ASLD through European Society.
• 05:07And by the US Preventive task force
• 05:10is a risk factor based screening.
• 05:13Tool specifically focusing on those
• 05:15who are are from endemic regions.
• 05:17Those who have HIV injection,
• 05:19drug users,
• 05:20MSM and either household or sexual
• 05:23contacts is my opinion and shared
• 05:25by many thought that if we're
• 05:26going to truly identify infected
• 05:28persons more readily that we must
• 05:30move towards an expansion of risk
• 05:32factor based screening or move
• 05:34fully to universal screening.
• 05:37Now the the reason that we care
• 05:39about hepatitis B ultimately is that
• 05:40this is social substantial morbidity
• 05:42mortality due to the development.
• 05:44This and liver failure and hepatitis
• 05:46B has a unique association with
• 05:48liver cancer in terms of turning
• 05:50it on a number of oncogenic genes
• 05:52that can lead to HCC in the absence
• 05:55of liver cirrhosis.
• 05:56And it is believed that nearly one
• 05:58in four individuals with chronic
• 06:00hepatitis B infection will die as a
• 06:03consequence of HPV related complications
• 06:04of for which HTC is most prominent.
• 06:06We do have a vaccine triptis B
• 06:09this is vaccine preventable and
• 06:11Jericho or convex three step series.
• 06:14And helpless tab is a recently approved
• 06:16two step series over one month.
• 06:18Now that it appears to be more
• 06:20immunogenic and we do have three
• 06:22oral nucleoside nucleotide analogs
• 06:23going to approve and license for
• 06:25the treatment hepatitis B,
• 06:26which are highly effective and
• 06:28suppression of the DNA but is not curative,
• 06:31as well as piglet interference,
• 06:32which is time limited and has
• 06:35similar efficacy but has substantial
• 06:38limitations due to tolerability.
• 06:41There are a number of therapies in phase one.
• 06:44Phase two development which are focused
• 06:46on functional cure of hepatitis
• 06:48B which has garnered substantial
• 06:50interests along several different classes,
• 06:52including earning interference core
• 06:54embitters, entering inhibitors,
• 06:55immunomodulators and virion egress
• 06:58inhibition,
• 06:58which we believe may help move
• 07:00the needle towards more
• 07:02effective cures for those who are
• 07:05chronically infected. Hepatitis C.
• 07:06This RNA virus with cute and chronic form.
• 07:09The burden is substantial globally
• 07:12estimated up to 71 million persons.
• 07:14And by the way, as recently as ten years ago,
• 07:17we've viewed this as nearly 170
• 07:19million persons, and so this is a
• 07:21significant shift in epidemiology.
• 07:23Hepatitis C, driven largely by two phenomena,
• 07:26one of which is increased burden
• 07:28of AC related death and liver
• 07:30cancer globally or last decade,
• 07:32many of whom have succumbed to their illness,
• 07:34and secondly due to the success of
• 07:36oral directly out of our leading
• 07:38to cure of a significant proportion
• 07:41of patients in the United States
• 07:43estimate about 2.7 million persons.
• 07:44Globally, nearly 700,000 deaths per year.
• 07:47Unfortunately at the same time
• 07:49that we're trying to eliminate,
• 07:51see through curative therapies,
• 07:53we have an actual increase in new
• 07:55incident infections globally and
• 07:57with the United States there remains
• 08:00substantial under diagnosis of
• 08:01hepatitis C and as we'll discuss in
• 08:04a moment now that there has been a
• 08:06shift in screen commendations in 2020
• 08:08from a risk factor based training
• 08:10focus on the baby boomers.
• 08:11Those born 1945 to 1965 and
• 08:13those with risk factors.
• 08:15To universal screening such that we
• 08:17are now suggesting that all all adults
• 08:19aged and older and all pregnant women
• 08:22should undergo A1 time Pepsi antibody
• 08:24test to identify the presence of hepatitis C.
• 08:27Slimmer peptides B there remains substantial
• 08:29morbidity mortality due to develop cirrhosis,
• 08:31liver failure and liver cancer.
• 08:33There is no vaccine for hepatitis C
• 08:35at this time, although there remains
• 08:37substantial interest terms.
• 08:38Investigation form for
• 08:40development of novel vaccines,
• 08:43but the success of these to date.
• 08:46Never made very,
• 08:47very limited.
• 08:48However,
• 08:49in regards to treatment,
• 08:50we are very fortunate that since
• 08:532014 there has been a proliferation
• 08:55of what now comprises 7 distinct FDA
• 08:58approved all oral interferon free
• 09:00regimens that are associated with
• 09:02viral cure and over 90% of patients
• 09:05which leads us to believe that hep C
• 09:08among these viruses is the most likely
• 09:11to be susceptible to elimination.
• 09:13There remains drug developments
• 09:14in the form of novel generic.
• 09:16Formulations as well as long
• 09:18acting injectables,
• 09:19which can lead to potential
• 09:21cure in one or two shots.
• 09:23Although the these have not yet reached
• 09:26late phase trials at this time,
• 09:29hepatitis delta is a satellite
• 09:31virus and RNA form,
• 09:33which occurs either as a convection
• 09:35or super infection of those already
• 09:37with hepatitis B and it requires both
• 09:40the surface antigen of hepatitis B
• 09:42and the large peptide delta antigen,
• 09:44and as such,
• 09:45unless you have hepatitis B first.
• 09:47You will not be susceptible to
• 09:49delta infection now.
• 09:50This is a significant
• 09:51underdiagnosed infection.
• 09:52We believe that the prevalence may be
• 09:55similar close to 5% of those conflicts,
• 09:59hepatitis B and globally.
• 10:00This amounts to up to 60 million
• 10:03persons and up to 125,000 persons
• 10:05here in the United States.
• 10:07Unfortunately,
• 10:07our current guidelines do not
• 10:09recommend screening all HIV infected
• 10:11individuals for hepatitis delta
• 10:13in the United States based
• 10:15on ASLD guidance, but recent.
• 10:17Updates to the European and the Asian
• 10:19Pacific guidelines have shifted to
• 10:22screening all persons with chronic HPV.
• 10:25We are hopeful that in the next
• 10:27iteration of guidance to United States,
• 10:29this may shift to universal testing
• 10:31of HIV infected individuals.
• 10:33Now, on top of the morbidity
• 10:35mortality that we articulate.
• 10:36Peptides, B, Delta,
• 10:38hepatitis further augments of the
• 10:40risk of cirrhosis, liver cancer,
• 10:43deliberative mortality.
• 10:44We estimate that up to 70%
• 10:46of persons with chronic.
• 10:48Delta develops cirrhosis within
• 10:5010 years of chronic infection and
• 10:52therefore is a source with even more
• 10:55significant morbidity and mortality.
• 10:57We do not currently have a vaccine for
• 10:59Delta and there is no FDA approved drug.
• 11:01However, Pegylated front is
• 11:03used as an off label therapy.
• 11:06We are very excited that there are
• 11:08several novel investigation agents
• 11:10currently in phase three development,
• 11:12which may offer new options within next
• 11:15several years and then finally peptides.
• 11:18E.
• 11:19This should be EV where the HAV is.
• 11:22A hepatitis is an RNA virus which
• 11:24also presents as an acute hepatitis
• 11:26with a low rate of fullman impact
• 11:28failure estimated about 0.5%.
• 11:30The global incidence is actually
• 11:32quite high and it's it's certainly
• 11:34underappreciated here in North America,
• 11:36but it may amount to up to
• 11:3820 million cases per year,
• 11:40up to 44,000 deaths.
• 11:41As of 2019,
• 11:43there appears to be endemic
• 11:44and very specific regions,
• 11:45particularly East and South Asia Middle East.
• 11:48Mexico, among other countries.
• 11:50There are six or seven distinct genotypes,
• 11:53four of which are applicable to humans.
• 11:55There are vectors in bore and camel species,
• 12:00and we have shared genetics with
• 12:03hepatitis E genotypes 3 and four,
• 12:07and this is actually a great consequence
• 12:09because we recognize that all of
• 12:11the case fatality rate is very low.
• 12:12Overall, it is extraordinarily high in women.
• 12:16In the third trimester pregnancy.
• 12:18For whom the case we tolerate is
• 12:21estimated to be as high as 25%,
• 12:23and this appears to be concentrated
• 12:25in genotype 3, hepatitis E.
• 12:27Furthermore,
• 12:28we are concerned that there have
• 12:30been a number of reports of
• 12:32chronic form peptides have emerged
• 12:34in immune compromised persons,
• 12:36namely those post transplant
• 12:38HIV infected with low CD,
• 12:404 count and those who have hematological
• 12:43cancers undergoing chemotherapy.
• 12:45And so these are cases that
• 12:47require careful attention.
• 12:48There is no.
• 12:52I'm afraid we need to wrap up very soon.
• 12:55OK, well and so. And finally we do
• 12:57have a treatment in the form of oral,
• 13:00proper variant, and so I'm going to skip
• 13:02here to the very end that we do have
• 13:06articulation of goals for hepatitis
• 13:08elimination in the United States.
• 13:10But this will require multimodal multi
• 13:12stakeholder engagement and and resource
• 13:15allocation for us to achieve this goal.
• 13:18And I believe that.
• 13:19The virus for which we think this is most
• 13:21feasible in a short entry term is peptide CI.
• 13:24Thank you very much for your attention.
• 13:25These are my knowledge events.
• 13:27I look forward to any questions
• 13:29during the cleaning session.
• 13:30Thank you.