>> WE WELCOME YOU TO ANOTHER
SESSION IN THE 21st YEAR IN A
COURSE CALLED DEMYSTIFYING
MEDICINE HELD AT THE NATIONAL
INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
THIS IS BASICALLY A COURSE IN
BRIDGE BUILDING CONNECTING
VARIOUS DISCIPLINES WITH THE
IDEA THAT IF PEOPLE COMMUNICATE
WITH ONE ANOTHER INTERESTING
IDEAS, NOVEL IDEAS AND PROGRESS
SMAED -- IS MADE IN CONNECTING
BIOLOGY, SCIENCE WITH DISEASE
AND WITH HUMAN HEALTH.
THE LOGO SHOWN IN THE UPPER
RIGHT IS THE BROOKLYN BRIDGE.
AND THE INDIVIDUALS ON THE
BRIDGE FOR TODAY'S PURPOSE ARE
DISCUSSING A SORT OF COMBINATION
OF BRIDGES.
ONE IS THE BRIDGE OF
SERENDIPITY.
THE OTHER IS THE BRIDGE OF
ADVANCES IN BASIC VIROLOGY AND
THE THIRD IS ITS APPLICATION
INTO SERIOUS ONGOING LIVER
DISEASE CAUSED BY VIRAL
HEPATITIS.
NOW, AS SHOWN ON THE SLIDE THE
SESSION MEETS FROM JANUARY TO
MID MAY.
THE CODE NUMBER FOR CME IS GIVEN
ON THE SLIDE AND ALSO THE
WEBSITE.
ALL THE PREVIOUS SESSIONS FROM
THE PREVIOUS SESSIONS ARE
ARCHIVED IN THE NIH VIDEO
ARCHIVE AND ACCESSIBLE AT ANY
TIME.
THE PURPOSE IS BRIDGING OF SILOS
OF INFORMATION INTO A MORE
COHESIVE COLLABORATIVE ARENA.
THIS IS THE INFORMATION FOR
THOSE WHO ARE APPLYING FOR CME.
THE NUMBER IS 52091.
MY HESITANCE IS AT THIS ANGLE I
CAN'T READ IT EXACTLY.
SO, VIRAL HEPATITIS HAS MANY
MANY LANDMARKS AND I'VE JUST
SELECTED A FEW OF THEM.
IT'S IN PART TO SHOW WHAT ROLE
THE NATIONAL INSTITUTES OF
HEALTH HAVE PLAYED IN THE
DISEASE.
IT WAS DESCRIBED BY HIPPOCRATES
AND VIRAL HEPATITIS IS MORE
ACUTE DUE TO HEPATITIS A.
IT'S NOT A LETHAL DISEASE YET
ITS ROLE IN HISTORY HAS BEEN
SUBSTANTIAL.
IN THE BATTLES OF THE PAST BOTH
SIDES CONDUCTING WARS HAD VIRAL
HEPATITIS AND AT THE BATTLE MUCH
GETTYSBURG NORTH AND SOUTH SIDE
THAT SUFFERED THIS DISEASE.
A REAL INFORMATION AND THE
CONCEPT A VIRUS COULD BE CAUSING
THE DISEASE WAS WRITTEN BY
LARGELY FRENCH CLINICAL
HEPATOLOGISTS.
THE REAL ADVANCE BEGAN IN 1955
WHEN STUDIES WERE CONDUCTED AT
WILLOW BROOK, AN INSTITUTIONAL
ESTABLISHMENT ON STATEN ISLAND
AND THERE IT WAS DOCUMENTED
THERE WERE TWO FORMS OF VIRAL
HEPATITIS DEPENDING ON THEIR
INCUBATION PERIOD.
THE SHORT FORM WHICH IS WHAT WAS
PRESENT AT WILLOW BROOK WAS
TRANSMITTED BY A FECAL-ORAL
ROUTE AND THE LONG INCUBATION
FORM WAS TRANSMITTED NOT IN THAT
STUDY BUT OTHERS LARGELY BY
BLOOD AND BLOOD PRODUCTS.
IN 1967 THE DISCOVERY OF AN
AUSTRALIAN ANTIGEN HEPATITIS B
OPENED THE FLOODGATES AND
DEFINED THE FIRST DEFINITIVE
HEPATITIS VIRUS.
THAT WAS DONE HERE AT THE
NATIONALS OF HEALTH AND
DR. BLUMBERG RESOURCED A NOBEL
PRIZE AND THERE'S A VACCINE BUT
UNFORTUNATELY IT'S NOT USED
WORLDWIDE FOR OTHER REASONS.
IN 1973 HERE AT THE NIH, STEVE
FEINSTONE IDENTIFIED SHORT
INCUBATION, HEPATITIS A NOW
CALLED INFECTIOUS HEPATITIS,
RARELY LETHAL, NON CHRONIC AND
MOST PEOPLE SURVIVE FROM IT.
ALMOST EVERYONE DOES.
IN 1989 HARVEY ALT PREPARED DICT
FROM STUDIES IN THE BLOCK BLOOD
BANK THERE WAS MORE THAN
HEPATITIS A AND IT WAS LABELLED
NON-A AND NON-B AND HEPATITIS C
SAY SERIOUS CHRONIC DISEASE AS
WELL.
IT'S ALSO THE ONLY VIRUS KNOWN
TO MANICURED BY A PHARMACEUTICAL
BUT THERE ARE PROBLEMS THERE
TOO.
SO BOTH HEPATITIS B AND
HEPATITIS C VIRUSES ARE MAJOR
CAUSES OF CHRONIC LIVER DISEASE
AND CHRONIC LIVER CANCER IS NOW
THE FIFTH MOST COMMON IN THE
UNITED STATES.
AND OF GREAT ADVANCE IS THAT THE
BLOOD BANK WAS RENDERED SAFE BY
THE HEPATITIS VIRUS.
THE DAYS OF HEPATITIS AFTER A
TRANSFUSION WERE ODD.
IN THINK ABOUT THIS THERE WERE
SEVERAL THOUGHTS THAT POPPED IN
MY MIND.
WE'LL HEAR SOMETHING ABOUT
TODAY.
CAN THE HEPATITIS VIRUSES MUTATE
LIKE A CORONAVIRUS PRODUCING NEW
INFECTION?
AND HOW DO THESE VIRUSES ENTER A
LIVER CELL?
HOW DO THEY REPLICATE?
HOW DO THEY LEAVE?
ARE THESE POTENTIAL THERAPEUTIC
TARGETS FOR THE FUTURE AND HOW
DO OTHER HEPATITIS PRODUCE
CIRRHOSIS AND ARE THERE NO
VACCINES FOR HEPATITIS B AND C
AND WHY ARE THEY STILL RAMPANT
IN THE WORLD DESPITE OUR
THERAPEUTIC ADVANCES?
TODAY WE'LL FOCUS ON THE
QUESTION OF DO WE KNOW THE VIRAL
HEPATIC CONDITIONS AND ARE THERE
OTHER HEPATIC HEPATITIS VIRUSES
FOR MAN AND THE ANSWER IS YES
THERE'S HEPATITIS D AND E AND
THEY'RE THE SUBJECT OF TODAY'S
DEMYSTIFYING MEDICINE.
SO OUR FIRST SPEAKER WHO WILL
TALK ABOUT HEPATITIS D IS THEO
HELLER IN THE TRANSLATIONAL
HEPATOLOGY SECTION OF THE LIVER
DISEASE BRANCH AND SENIOR
INVESTIGATOR.
HE HAS BEEN INTERESTED IN
CLINICAL RESEARCH, MICROBIOLOGY
AND INFECTIOUS DISEASE, SYSTEMS
OF BIOLOGY, MOLECULAR BIOLOGY
AND APPLIED BIO CHEMISTRY.
THEO GRADUATED FROM MEDICAL
SCHOOL IN SOUTH AFRICA AND DID
HIS RESIDENCY AT GEORGETOWN HERE
IN WASHINGTON, D.C. AND A
POST-DOCTORAL FELLOWSHIP AT THE
NATIONAL INSTITUTE OF HEALTH.
A GASTROENTEROLOGY FELLOWSHIP AT
THE UNIVERSITY OF MARYLAND AND
THEN ANOTHER HEPATOLOGY SPECIFIC
FELLOWSHIP HERE AT NIDDK.
SO OUR SECOND SPEAKER IS MARK
GHANY WHO RECEIVED HIS MEDICAL
DEGREE FROM IRELAND AND MASTER
OF HEALTH SCIENCES AT DUKE
UNIVERSITY FELLOWSHIP AT TULANE
AND THERE HE WAS A CLINICAL
INSTRUCTOR THEN CAME TO THE NIH
IN 1996 AS A MEDICAL STAFF
FELLOW AND IS A STAFF CLINICIAN
AT THE PRESENT TIME AND SECTION
CHIEF OF THE CLINICAL HEPATOLOGY
RESEARCH SECTION OF THE LIVER
DISEASE BRANCH HERE IN THE
CLINICAL CENTER.
HIS MAIN INTERESTS ARE IN
RESEARCH AND EPIDEMIOLOGY AND
HE'LL BE DISCUSSING HEPATITIS E.
SO WE URGE YOU TO SUBMIT
QUESTIONS ON YOUR COMPUTER
THERE'S AN INDICATION WHERE YOU
CAN SUBMIT IT AND THEY'LL BE
ANSWERED AND DISCUSSED IN A
QUESTION AND ANSWER PERIOD THAT
WILL FOLLOW THE TWO
PRESENTATIONS.
SO THEO, WOULD YOU BEGIN,
PLEASE.
>> IT'S THE LESS APPRECIATED
THOUGHT OF VIRUS BOTH OF THEM
TODAY, HEPATITIS D AND E AND
WE'LL TRY TO HIGHLIGHT SOME OF
THE REASONS WHY THIS SHOULDN'T
BE THE CASE.
MY DISCLOSURES I WANT TO
ELIMINATE HEPATITIS D AND
OBSESSED WITH LIVER DISEASE AND
START THE DAY WITH COFFEE AND
HAVE NO FINANCIAL DISCLOSURES
AND WE LOOK TO APPROACH PATIENTS
WITH HEPATITIS D AND THE
UPCOMING RESOLUTION TO CURE
HEPATITIS D.
THERE'S A PARADIGM SHIFT.
WHAT IS HEPATITIS D IT WAS
DISCOVERED BY SERENDIPITY AND IT
WAS THE STORY WITH THE BRIDGE
AND IT WAS IN A SEMINOLE PAPER
AND BEFORE TALKING ABOUT
HEPATITIS D IT'S ABLE TO SAY
VACCINATION IS AYE THE ULTIMATE
CURE BUT IT IS FOR HEPATITIS D.
IF WE COULD VACCINE EVERYONE FOR
HEPATITIS B WE'D BE RID OF B.
WHY DO WE CARE ABOUT HEPATITIS
D, 50% DEVELOP CIRRHOSIS WITH
HEPATITIS D AND THE HIGHER RANGE
OF 20% TO 20 YEARS INCREASED
RISK OF HCC HEPATOCARCINOMA
THREE FOLD HIGHER AND WHY SHOULD
WE CARE?
IF IT'S SUCH A BAD DISEASE AN
NOTHING TO DO WE COULDN'T CARE
BUT I WANT TO HIGHLIGHT A COUPLE
THINGS ALL FROM THE CLINICAL
CENTER.
THERE WAS A STUDY TREATING 13
PATIENTS AND THREE CONVERTED
WITHIN FIVE YEARS AND AFTER
ALMOST NINE YEAR OF FOLLOW UP
SIX OF SEVEN WERE ALIVE AND
PERHAPS THE FIRST EVIDENCE FOR
RESOLUTION ARE OF SORCIRRHOSIS
SINGLE PATIENT WAS TREATED IN
THE '90s WITH CHRONIC HEPATITIS
D AND THIS WAS PUBLISHED AND IN
PANEL A, YOU CAN SEE THE
NODULES.
IN B YOU SEE BRIDGING FIBROSIS
AND GRADUAL RESOLUTION.
SO YOU GET TO D WHICH IS
ESSENTIALLY A NORMAL LIVER
BIOPSY.
THIS GIVES THE IMPORTANT OF WHY
AND FINDING PATIENTS AND
TREATING AND THE FIRST
ILLUSTRATION DOCUMENTED OF
RESOLUTION OF CIRRHOSIS.
WHY DO WE TREAT?
THE REAL REASON IS TO TREAT FOR
DEATH.
EVERYTHING ELSE IS A SURROGATE
AND WE LOOK AT CONVERSION AND
HEPATITIS D RNA LOSS AS A
FURTHER EMPHASIS, THREE YEARS
AGO THEY PUBLISHED 25% OF
SURFACE ANTIGEN TRANSPLANT
PATIENTS IN EUROPE WERE
HEPATITIS D POSITIVE MORE THAN
FIVE TIMES THE PROPORTION YOU'D
EXPECT.
IT'S VERY SIMPLE.
TEST EVERYONE ONCE AND USE
ANTIBODY AND CONFIRM WITH PCR.
LET'S TALK DEEPER BECAUSE THE
EPIDEMIOLOGY WILL INFORM THE
WHO.
SHOULD WE COMPARE EVERYBODY TO
HIGH RISK VERSUS LOW RISK AND
VARIABILITY AND THE LACK OF
TESTING AND THIS IS ONE OF MY
FAVORITE PARAGRAPHS IN THE FIELD
WRITTEN BY DR. ROSSETTA DESPITE
THE GLOBAL SURVEYS THE GLOBAL
NUMBER REMAIN UNDEFINED AN
ESTIMATES RANGE FROM 12 MILLION
TO 75 MILLION AN TELLS YOU HOW
LITTLE RIGOR THERE'S BEEN IN THE
FIELD AND THE FIGURES EMPHASIZE
THE REPORTS ON HEPATITIS D AND
LACK OF SUFFICIENT QUALITY DATA
THUS INADEQUATE SCREENING AND
LIMITATIONS AND LACK OF TESTING
HAVE IMPANCTED HOW WE SEE
HEPATITIS D.
THIS IS A MAP SHOWING HOT SPOTS
IN RED, YELLOW INTERMEDIATE AND
GREEN LOW AND BLUE VERY LOW AND
DIFFERENT GENOTYPES.
THIS IS IMPORTANT BECAUSE THEY
DIFFER GLOBALLY AND HAVE
DIFFERENT DETECTION RATES WITH
DIFFERENT ASSAYS AND HOT SPOTS
THINK THE PREVALENCE OF
INCIDENTS OF HEPATITIS D.
THIS IS A STUDY FROM THE
CLINICAL CENTER.
WE LOOKED AT 588 PATIENTS WITH
CLEAR RESPECTIVE FOR HEPATITIS D
AND DID A MULTIVARIATE ANALYSIS
AND THERE WERE HEPATITIS D THAT
WAS DOMINANT.
ALT WAS HIGH.
PEOPLE WHO INJECTED DRUGS AND
MOST IMPORTANT TODAY IN EUROPE
AND NORTH AMERICA ENDEMIC
COUNTRY OF ORIGINS THE HOT
SPOTS.
IF YOU'RE SURFACE ANTIGEN
POSITIVE YOU SHOULD BE SCREENED
FOR HEPATITIS D AND/OR HIV.
THE AMERICAN GUIDELINES SAY IF
HEPATITIS B VIRAL LEVELS ARE LOW
OR IF YOU'RE AT RISK FOR
HEPATITIS D AND THERE'S A LONG
LIST OF RISK FACTORS YOU CAN
IMAGINE EVERY PRIMARY CARE GOING
FLEW -- THROUGH WITH PATIENTS IN
THEIR OFFICE WHEN THEY HAVE FIVE
MINUTES WITH THEIR PATIENT.
THIS IS WHERE THE FIELD STANDS.
A PATIENT, 49-YEAR-OLD MAN BORN
IN IDAHO, MARRIED WITH TWO
CHILDREN, UPSTANDING CITIZENS
INVOLVED WITH COMMUNITY
ACTIVITIES HAD HIS COLONOSCOPY.
THE GASTROENTEROLOGIST NOTED HIS
LEVELS WERE ELEVATE AND E
ANTIGEN WAS POSITIVE SO HE
TREATED HIM FOR HEPATITIS B BUT
THE PATIENT WENT ON TO DEVELOP
CHOLANGIOCARCINOMA AND ANOTHER
CLINICIAN FOUND HE WAS HEPATITIS
B POSITIVE AND I KNOW WHAT
YOU'RE THINK.
YOU'RE THINK, THAT'S NICE, THEO
BUT IT'S AN ANECDOTE.
IT'S NOT TRUE.
OKAY.
LET'S LOOK AT THE VIRAL B LEVELS
AND WHICH VIRUS WAS DOMINANT AND
IT WAS ALMOST EVENLY SPLIT THE
BETWEEN B AND D AND THEY LOOKED
AT THE DNA LEVELS AND AGAIN IT
WAS NOT THE SORT OF DOMINANCE
YOU WOULD EXPECT.
44% AND 39% WERE NOT HEPATITIS D
DOMINANT.
IN TERMS OF DOMINANCE AND
HEPATITIS B DNA LEVELS IS NOT
HOW THE VIRUS BEHAVES HALF THE
TIME.
WHAT ABOUT THE RULES AN
GUIDELINE?
T
TATIANA KUSHNER LOOKED AT THE
SYSTEM WITH PATIENT WERE SIR FAS
B POSITIVE AND FOUND 8.5% WERE
SCREENED.
SHE FOUND OF THOSE SCREENED,
3.4% WERE POSITIVE WHICH ISN'T
WHAT WE'D EXPECT, 2 TO 5% AND OF
THOSE POSITIVE ONLY 8.2% HAD RNA
CHECKED.
EVEN WHEN THEY HAD A POSITIVE
RESPONSE THEY IGNORED IT AND 80%
OF PATIENTS WITH A HIGH RISK
PROFILE WERE NOT TESTED.
IT'S 796.25.
I ROUND THE OFF TO 796.
WHAT ABOUT WHEN WE DO FOLLOW THE
RULES?
I SHOWED THE DEFINITION BY
FOLLOWING THIS IT'S NOT USEFUL
AND WE DON'T FOLLOW OUR OWN
RULES OF HIGH RISK PATIENTS BUT
WHEN FOLLOW THE RULES THIS IS A
FANTASTIC STUDY FROM EUROPE.
PRIOR TO REFLEX TESTING ONLY
7.6% WERE TESTED IN THE POSITIVE
TESTING AND THE AMOUNT OF
POSITIVE QUINTUPLES.
MANY DID NOT HAVE A LONG LIST
RISK FACTORS AND THIS IS TEXT
FROM THE VISUAL ABSTRACT.
SCREENING VIRUS FACTORS IS SUB
OPTIMAL.
SO 40% HAVE LEVELS AND DON'T
TEST THOSE WITH DOCUMENTED HIGH
RISK AND 60% HAVE NO RISK
FACTORS.
SO I WANT TO DIGRESS A LITTLE
BIT AND TALK ABOUT THE HEPATITIS
B VACCINATION EFFORT.
IN 1981 IT WAS LICENSED AND
RECOMMENDED FOR HIGH RISK GROUPS
SUCH AS INFANTS WHOSE MOTHERS
WERE POSITIVE AND THINGS LIKE
THAT.
IF YOU LOOK AT THE TIME IT
DIDN'T DO MUCH TO THE INCIDENTS
OF HEPATITIS B.
IN 1991 THEY SAID THIS IS NOT
WORKING LET'S IMMUNIZE EVERYBODY
AND HEPATITIS B WAS VIRTUALLY
ELIMINATED IN CHILDREN LESS THAN
18 YEARS OF AGE AND HPV THE
GUIDELINE SAID LET'S ONLY
VACCINE ADOLESCENT FEMALES?
WELL, WHERE ARE THEY GETTING THE
HPV FROM AND WE REALIZED WE'RE
NOT THAT SMART AND WE CAN GO
THROUGH OTHER ILLUSTRATIONS.
HISTORY DOESN'T ALWAYS REPEAT.
SOMETIMES IT JUST SCREAMS.
WHY DON'T YOU LISTEN TO ME AND
FLY WITH THE BIG STICK.
I HAVE TO SUGGEST THE GUIDELINES
ARE NOT APPROPRIATE.
SO WHO SHOULD BE TESTED?
EVERYONE WITH HEPATITIS B
IMAGINE A WORLD WITH NO DELTA
WOULD BE SOMETHING REALLY
DIFFERENT.
A BOOK THE ARTS AND POLITICS OF
YOU CAN'T STUDY OR TREAT
ANYTHING IF YOU DON'T KNOW HOW
TO MEASURE IT AND MANY KNONO NO
PRIZES HAVE BEEN GIVEN JUST FOR
THE ABILITY TO MEASURE AND GOES
TO UNIVERSAL TESTING AND WE TEST
THE DOG AND WE FOUND IT'S
POSITIVE AND YOU THINK FEDERAL
EMPLOYEES SIP ON MINT TEA AND
EAT GODIVA SO ONE DAY WHILE
SITTING AT HOME WE LOOKED AT A
MALE WHO LIVES AND WORKS IN
CHICAGO AND REFERRED FOR
HEPATI
HEPATITIS B AND WAS SURFACE
ANTIGEN POSITIVE AND ANTIBODY
POSITIVE.
HE'S MORE TYPICAL AND IT WAS
ANTIGEN NEGATIVE AND LIVER
BIOPSY WAS IMPRESSIVE, 14 OF 18
FOR INFLAMMATORY SCORE AND 3 OF
6 BRIDGING FIBROSIS AND IS A
HEPATIC VENOUS PRESSURE GRADIENT
THE PORTAL PRESSURE SURROGATE
WAS 8 MILL METERS WHICH IS
ELEVATED.
NOR THAN 10 TO 12 IS
SIGNIFICANT.
THE FIRST QUESTION THE PATIENT
ASKS IS CAN I GIVE IS TO ANYONE
ELSE.
THAT'S HIS FEAR.
WE SHOULDN'T FORGET THE
GUIDELINES.
BLOOD AND BODY FLUIDS.
CO-INFECTION WHERE PATIENTS GET
HEPATITIS B AND D AT THE SAME
TIME AND PEOPLE BECOME CHRONIC
AND PEOPLE GET HEPATITIS B AND
THEN GET B AND 90% BECOME
CHRONIC AND THAT'S OFTEN MISSED.
WHAT'S NEXT?
WE NEED TO GO BACK TO BASICS.
HEPATITIS B IS DIFFICULT TO
UNDERSTAND.
1700 NUCLEOTIDES.
THE SMALLEST PATHOGENIC VIRUS IN
HUMANS.
IT'S CLOSED AND BROAD SHAPED AND
SURROUNDED BY HEPATITIS D LARGE
AND SMALL ANTIGEN AND THE ONLY
VIRUS IT CODES FOR.
IT DOESN'T CODE FOR ANYTHING
ELSE.
ANY SELF-RESPECTING VIRUS CODES
FOR POLYMERASE AND ALL IT CODES
FOR IS IT'S OWN CODE PROTEINS
AND ENCASED IN HEPATITIS B
ENVELOPE LIKE THE WOLF IN
SHEEP'S CLOTHING NOTE THAT IT'S
A SHEEP BUT HEPATITIS D IS FAR
WORSE AND INSERTS ITSELF IN THE
HEPATITIS B ENVELOPE AND
WHENEVER I HEAR THIS I ALWAYS
WANT TO KNOW HOW DOES THIS
HAPPEN.
THIS IS THE VIRAL RNA AND A
NUCLEOTIDE AND ADAR1 IS AN
PROTEIN MADE IN RESPONSE TO
INTERFERON AND CAUSES CHAOS
MUTATIONS BUT HERE IT CAUSES A
CHANGE FROM UAG TO A TRYPTOPHAN
AND ALLOWS THE PROTEIN TO BE
EXTENDED BY APPROXIMATELY 17 TO
19 AMINO ACIDS DEPENDING ON THE
GENOTYPE AND THAT SITE IS VERY
IMPORTANT IN TERMS OF THERAPY
BUT ALSO IMPORTANT IN TERMS OF
BEING ABLE TO PACKAGE INTO
HEPATITIS B OTHERWISE THE VIRUS
COULDN'T BE PACKAGED.
HOW DID THE VIRUS KNOW TO TAKE
ADVANTAGE OF POLYMERASE AND
REPLICATE IT'S DIABOLICAL.
THE PATIENT IS OTHERWISE
HEALTHY.
SO IDEALLY WE'D LIKE TO TREAT
HIM BUT WITH WHAT THERAPY
>> LET'S GET A LITTLE BIT OF
HISTORY.
AT THE CLINICAL CENTER PATIENTS
TREATED WITH INTERFERON AND THE
FIRST PAPERS THAT CAME OUT IN
1987 AND THIS IS PAGE 291 TO 298
AND 299 TO 303 IN THE FIRST
JOURNAL.
THE FIRST TWO GROUPS WHO
PUBLISHED TREATMENT OF HEPATITIS
D WITH INTERFERON AND I WANT TO
RUN THROUGH SIM KNOLL STUDIES.
INTERFERON WITH AND WITHOUT
HEPATITIS B THERAPIES AN
LONG-TERM.
PATIENTS WERE TREATED WITH A
GIVEN AMOUNT OF UNITS AND THE
VIRAL RNA AND COMPLETE, BOTH
RESPONSES.
AND YOU CAN SEE A CLEAR DOSE
RESPONSE CURVE THERE.
50 PERFORMANCE OF THE HIGH DOSE
COMPLETE RESPONSE AND 0% WITH
PLACEBO AND A RELAPSE IS COMMON
AFTER TREATMENT HAS BEEN
STOPPED.
LONGER FOLLOW-UP OF 36 OF THE
PREVIOUS PATIENTS SURVIVAL WAS
STATISTICALLY IN FAVOR OF THE
HIGH DOSE VERSUS LOW DOSE AND
HIGH DOSE WAS CONTROLS.
IN FACT MOST CONTROLS HAD DIED.
THAT'S WHY THOSE PATIENTS COULD
NOT BE FOLLOWED.
FEW PATIENTS WERE LOST TO FOLLOW
UP AND FOUR WITH CIRRHOSIS
CONFIRM
CONFIRMING WHAT WAS DISCOVERED
IN THE '90s.
THE BOTTOM LINE SIN TERMS OF
WHAT WE USED TO CALL SUSTAINED
VIROLOGICAL RESPONSE AND NOW
DURABLE VIROLOG CAL RESPONSE IS
30% TO 20% WILL RESPOND.
WE CAN DO BETTER.
JUST A REMINDER ABOUT THE
LONG-TERM TREATMENT I SHOWED YOU
IN THE BEGINNING AND WHAT THAT
MEANS, INTERFERON COULD BE
TWEAKED IN DIFFERENT WAYS BUT
AGAIN NOT EVERYONE RESPONDED.
THERE WERE DIFFERENT GENOTYPES.
MANY GENOTYPE 1 WHICH IS MAINLY
THE WEST.
DIFFERENT RNA ASSAYS ARE
DIFFICULT TO COMPARE ACROSS
ASSESSES AND WHAT LOOKS LIKE
RELAPSE IS NOT RELAPSE BUT
ININSENSITIVE ASSAY AND THE
DIFFERENT GENOTYPES ARE 5 TO 8
ARE DIFFICULT TO DETECT WITH THE
RNA ASSAYS.
PATIENTS SHOULD BE SCREENED AND
THEY SHOULD BE WARNED THERE'S NO
VACCINE AND THEY'RE VULNERABLE
TO SUPER INFECTION.
WHAT ABOUT ANTI-HEPATITIS B
STUDY?
THE FIRST WAS DONE AT HERE AT
THE CLINICAL CENTER.
OTHERS INCLUDING IN THE NEW
ENGLAND JOURNAL SO IT MUST BE
TRUE.
ALL OF THEM SHOWED TREATING
HEPATITIS B ALONE DOESN'T WORK.
WHAT ABOUT TREATMENT GUIDELINES?
THERE'S NO CURRENT FDA APPROVED
THERAPY FOR HEPATITIS D.
AND THE AMERICAN ASSOCIATION FOR
THE STUDY OF LOWER DISEASE SAID
A LOW DOSE OF INTERFERON IS
RECOMMENDED FOR IS IT MONTHS AND
IF HEPATITIS B LEVELS ARE
INCREASED TREATMENT SHOULD BE
PERFOR
PERFORMED WE TREAT EVEN WHEN
LEVELS ARE NOT INCREASED AND
GIVEN THE EFFICACY OF CURRENT
THERAPIES IT'S REASONABLE TO
REFER FOR STUDIES AND
EXPERIMENTAL STUDIES.
ALL THE STUDIES, ALL THE DRUGS
I'M GOING DISCUSS HAVE BEEN A
TRIUMPH OF SCIENCE.
REALLY AND TRULY NOT POSSIBLE
WITHOUT A DEEP INFORMATION OF
BASIC SCIENCE AND BIOLOGY AND
THOSE OF US ON THE CLINICAL SIDE
ARE DISMISSIVE OF THE BASIC
SCIENTISTS.
THAT'S A REAL MISTAKE BECAUSE
NONE OF THIS WOULD BE POSSIBLE
WITHOUT THE BASIC SCIENCE AND IT
MAY TAKE A WHILE FOR THE
EVIDENCE TO BECOME CLEAR BUT
EVENTU
EVENTUALLY.
EEL TALK ABOUT A COUPLE
THERAPIES AND NUCLEIC ACID
POLYMERS AND THERE ARE OTHERS
BUT THESE ARE FURTHEST ALONG.
IS MUCH OF THE DATA I'LL PRESENT
IS IN ABSTRACT FORM AND I'LL
FOCUS ON THE HIGHLIGHTS AND
BECAUSE OF THE NATURE OF THE
STUDIES FOCUS HAS BEEN ON
SURROGATES AND REMEMBER THE REAL
END POINT IS DEATH.
THEN THE SURROGATE FOR DEATH
WOULD BE HCG CIRRHOSIS AND THE
SURROGATE WOULD BE ELIMINATING
THE VIRUS AND AS A SURROGATE FOR
THAT, WE USE THE 2 LOG DECLINE
OF HDV AND WHAT ARE DURABLE VIR
LOGIC RESPONSE AND WHEN YOU USE
THE SUR GALT OF A SURROGATE YOU
GET INTO TROUBLE AND -- A LARGE
STUDY WAS STOPPED BECAUSE OF
ADVERSE OUTCOMES.
IT'S NOT CLEAR WHETHER IT WILL
COME BACK OR NOT BUT I'D LIKE TO
STILL GO THROUGH IT BECAUSE IT'S
IMPORTANT.
IT'S A TYPE 3 INTERFERON IT HAS
LESS THOUGHT EFFECTS BECAUSE OF
A GREATER HEPATIC RESTRICTION.
AND THE ONE STUDY FOR HEPATITIS
B WAS A STUDY WITH LAMDA AND 36%
OF PATIENTS HAD CLEARED RNA AND
NORMAL ALT AND THE CURVE SHOWS
THE RESPONSE DIFFERENCES.
WHAT ABOUT INHIBITORS.
THESE ARE LIKELY TO BE THE FIRST
DRUGS APPROVED FOR HEPATITIS B
IN THE UNITED STATES.
THE TRANSPORTER PEPTIDE THE
SYSTEM IS THE RECEPTOR FOR
HEPATITIS B AND IT'S POSSIBLE TO
BLOCK THAT AND BLOCK IT FROM
GOING INTO CELLS THUS BLOCKING
HEPATITIS D AND SHOWED
INHIBITION OF HEPATITIS B AND D
ENTRY.
I'LL SHOW THE NEW ENGLAND STUDY
FROM LAST YEAR.
IF YOU LOOK AT THE TOP CURVE
PLACEBO SHOWED NO DECREASE IN
VIRAL LEVEL AND THE 2 AND 10 MIL
GRAM DOSES HAD 2.5 AND 1.9
LEVEL.
SOME OF PATIENTS STOP CLEAR BUT
FOR THE MAJORITY IT'S NOT THE
CASE AND IF YOU LOOK AT
NORMALIZATION OF ALT IT'S JUST
ABOVE 50% FOR BOTH DOSES.
THIS IS VERY EXCITING AND WE
HAVE ACTIVITIES ACROSS AN ARRAY
OF AGENTS AND MECHANISMS ARE NOT
COMPLETELY UNDERSTOOD.
I WANTED TO HIGHLIGHT ONE STUDY
PUBLISHED SEVEN YEARS AGO USING
REP 2 39 IN IT'S A COMPLICATED
DOSING.
500 MILLIGRAM FOR 15 WEEKS AND
PEG INTERFERON FOR 33 WEEKS AND
THE MEAN DECLINE WAS 5.34 BLOGS
AND SOME WERE HEPATITIS B
NEGATIVE AND SURFACE ANTIGEN
NEGATIVE.
AT ONE YEAR 58% WERE HEPATITIS D
RNA NEGATIVE AND AT 3 1/2 YEARS
7 OF 12 WERE NEGATIVE AND WE'RE
WAITING FOR OTHER STUDIES BUT
THIS WOULD ALSO BE EXCITING.
I MENTIONED WHEN THE PROTEIN
GETS EXTENDED FROM SMALL TO
LARGE ANTIGEN IT HAS A SITE AND
THE INHIBITORS DEVELOP FOR RAS
ONCA GENES AND ADAPTED AND
THERE'S A PAPER FOR RSV AND
THERE'S LIPIDS TO PROTEINS AND
THIS PROMOTES MEMBRANE IN TO
INTERACTIONS AND FOR MULTIPLE
CELLULAR PROTEINS INSERTING
THEMSELVES TO HEPATITIS B AND
THEY AVOID THE G.I. SIDE EFFECTS
OF GIVING A HIGH DOSE OF
RITONAVIR AND IF YOU LOOK AT
THIS, 11 OF 22 PATIENTS AT 24
WEEKS WERE UNDETECTABLE ABOVE
LIMITATION FOR HEPATITIS D RNA
AND SIX WERE MORE THAN A TWO LOG
DECLINE A SURROGATE ACCEPTED
MARKER FOR THE PAPER AND LESS
THAN FIVE HAD A TWO-LOG DECLINE.
THIS IS ALSO PROMISING AND
EXCITING.
THE LIGANDS AND LOTS OF OTHER
SILENCING RNAs AND OTHER THINGS
COMING.
AND THE RNA DE KWLIEND BUT DID
NOT BECOME UNDETECTABLE AND
IMPROVED AND THERAPY AND ALL
RETURNED TO BASELINE AFTER THE
CONTINUING THERAPY.
THIS IS A TYPICAL STORY.
THE PATIENT SIT IN YOUR OFFICE
AND SAYS NOW WHAT, DOCTOR?
AND HE BECAME NEGATIVE BUT
RELAPSED AFTER TREATMENT.
THEN HE SAYS, WHAT'S NEXT NOW?
CLINICAL TRIAL.gov THERE'S ABOUT
61 STUDIES NOW.
NOT ALL ARE ACTIVE, SOME ARE
COMPLETED.
NOT ALL ARE REALLY THERAPEUTIC
BUT THERE'S A BIG DIFFERENCE IN
JUST A FEW YEARS.
SO HEPATITIS D IS FASCINATING.
NEARLY 50 YEARS LATER WE'RE
STILL STRUGGLING.
PEGINTERFERON IS LIKELY TO
BECOME A COMPONENT FOR A WHILE
EVEN WITH THE INTENT TO GIVE
WITH INTERFERON AND WE FLARES
NOT OUTCOMES AND LOOK AT
PROGRESS AND HERE I HAVE TO
MENTION ALSO MATHEMATICAL MODEL
AND WE LOOKED AT LOYOLA AND
THAT'S GUIDED THE APPROACH TO
HOW WE TREAT PATIENTS.
AND THESE NOVEL THERAPIES HOLD
REAL PROMISE.
YOU'LL SEE THIS PAINTING IN THE
BACK WALL WALKING FROM THE BACK
NOT WHERE THE PATIENTS COME IN.
THIS IS A PAINTING HUNG IN THE
CLINIC A PATIENT GAVE HIM.
I WANT YOU TO STOP FOR A SECOND
AN THINK HOW IT MAKES YOU FEEL.
YOU MAY ASK WHY WOULD YOU HANG
SINCE A CLINIC.
IT'S SUCH A DE PRESSING THING.
THE ANSWER IS IT'S NOT DEPR
DEPRESSING IT'S INSPIRING.
OUR FAILURES SHOULD CHALLENGE US
TO DO BETTER.
THERE'S NO DISHONORING FAILURE
BUT IN TRYING AND WE'RE HERE TO
MAKE THE WORLD BETTER AND TO TRY
TO DO THAT AND FOR ME WHEN I
WALK THE PAINTING INTO CLINIC
IT'S AN INSPIRATION TO STRIVE TO
DO BETTER AND THINK BETTER AND
TRY HARDER.
I THINK THIS IS VERY FITTING AND
VERY APPROPRIATE AND BASED ON
THIS, IT'S INCREDIBLE TO STAND
HERE 40 YEARS LATER AND TALK
ABOUT A REVOLUTION IN THERAPY.
I WANT TO THANK THE PATIENTS WHO
REALLY VOLUNTEER EVERYTHING,
GIVE THEMSELVES THE BLOOD, THE
LIVER, THE RESEARCHERS WE WORK
WITH.
NOTHING WITHOUT BEING POSSIBLE
WITHOUT THE RESEARCHERS.
THEY MAKE EVERYTHING HAPPEN.
THE FELLOWS WHO DO THE BULK OF
THE WORK.
ALL THE COLLABORATORS AND MY
PARTNER IN CRIME.
DR. KLEINER AND MY MENTORS I
INCLUDE THE PICTURE BECAUSE OUR
FEARLESS LEADERS AND THERE'S
DR. ARIAS WHO ATTENDS OUR ROUNDS
REGULARLY AND HAS A LOT TO SAY.
I WANT TO END WITH THIS PATIENT
AGAIN.
THE FIRST PATIENT TO BE SHOWN TO
HAVE CIRRHOSIS REGRESS AND IT'S
POSSIBLE BY THE DREAMS AND MY
EDI
IDEAL IS TO TAKE IT FROM THE
PATIENT LEVEL TO THE POPULATION
LEVEL.
THANK YOU FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH.
MAY I REMIND EVERYBODY, PLEASE
TO SUBMIT THEIR QUESTIONS
ELECTRONICALLY IF YOU'RE
WATCHING THIS VISUALLY AND THE
SECOND SPEAKER IS MARC GHANY TO
TELL US ABOUT HEPATITIS E.
>> GREAT.
WE'RE MOVING DOWN THE HEPATITIS
ALPHABET.
NO LESS IMPORTANT VIRUS, I MIGHT
ADD.
I'LL ALSO BEGIN WITH A CASE THAT
WILL ILLUSTRATE THE CLINICAL
DISEASE OF THE VIRUS I'M GOING
TO TALK ABOUT AND A 42-YEAR-OLD
FEMALE WAS REFERRED TO US DUE TO
A TEST WITH THE HEALTH OF HER
LIVER AND HER PRESENTATION WAS
100, FOUR TIMES NORMAL AND
COMPLAINED OF MILD FATIGUE WAS
HER ONLY SYSTEM AND HER AILITY
PEAKED AND DEVELOPED JUANDICE
WITH A BILIRUBIN LEVEL WAS 2500
AND SUBSEQUENTLY TESTED POSITIVE
FOR HEPATITIS E AND HEV AND RNA
AND GENOTYPE 3.
THE ONLY RISK FACTOR WE COULD
IDENTIFY WAS A SCALPEL INJURY
AND EXPOSURE TO PIG BLOOD AND
DENIED FOREIGN TRAVEL OR
INGESTION OF PORK OR GAME AND
LEL LET ME TELL BUT HEPATITIS E
IT'S BEEN ESTIMATED OVER 900
BILLION PERSONS HAVE BEEN
INFECTED TRANSLATES TO 1 IN 8
PEOPLE ON THE PLANET AND
ESTIMATED THERE'S ABOUT 20
MILLION INCIDENT INFECTIONS
RESULTING IN 70,000 DEATHS AND
MOST DO NOT PRESENT WITH
JUANDICE AND RESULTS WITHOUT
LONG-TERM SEQUELAE BUT SEVERE
CASES WITH JUANDICE CAN OCCUR
THOSE WITH IMMUNODEFICIENCY AND
PEOPLE IN PREEXISTING DISEASE
AND PREGNANT WOMEN.
INTERESTINGLY, CASES OF CHRONIC
INFECTION HAVE BEGUN TO BE
DESCRIBED PRIMARILY IN
IMMUNOSUPPRESSED INDIVIDUALS AND
TRANS PLANT RECIPIENTS.
PATIENTS ON CANCER CHEMOTHERAPY
AND THOSE INFECTED WITH HIV.
SOME HISTORICAL PERSPECTIVES.
THE VIRUS CAME ON THE MEDICAL
RADAR IN 1978 WHEN THERE WAS A
LARGE OUTBREAK OF JUANDICE IN
KAS MIR, INDIA AND IT WAS
THOUGHT TO BE ENTERICALLY
TRANSMITTED NON-A AND NON-B
HEPATITIS AND AFFECTED PERSONS
OF 15 TO 45 AND A SELF-LIMITED
HEPATITIS BUT HAD A HIGH
MATERNAL AND FETAL MORTALITY AND
LATER THOUGHT TO CAUSE
EPIDEMIOLOGY AND SPORADIC CASES
OF HEPATITIS.
THERE WAS A SECOND OUTBREAK OF
HEPATITIS THAT OCCURRED IN A
RUSSIAN MILITARY CAMP IN
AFGHANISTAN AND A CAMP DOCTOR
TOOK IT UPON HIMSELF TO INGEST
STOOL EXTRACTS FROM INFECTED
PATIENTS AND FIVE WEEKS LATER HE
DEVELOPED SEVERE ACUTE VIRUS AND
VIRUS LIKE PARTICLES WERE
OBSERVED FROM STOOL COLLECTED ON
THE DAYS FOLLOWING INGESTION AND
HIS STOOL WAS LATER USED TO
INFECT THE CHIMPANZEE CONFIRMING
IT WAS DUE TO A MICROORGANISM
AND IN 1990 THERE WAS A
PARTIALLY CLONED VIRUS AND THEN
IT THE GENOME WAS SEQUENCED AND
THE FIRST SEROLOGIC ASSAY WAS
DEVELOPED AND THE TAXOLOGY HAS
CHANGED AND IT BELONGS TO A
SINGLE FAMILY AND THERE'S TWO
SUBFAMILIES.
THERE ARE FIVE GENERA AND NINE
SUBSPECIES.
THE MOST IMPORTANT IS THE TWO
SPECIES NAMED AFTER THE PERSON
WHO DISCOVERED THE VIRUS AND
THERE'S EIGHT GENOTYPES.
FIVE OF WHICH INFECT HUMANS.
1 IN 2 ONLY INFECT HUMANS AND 3,
4 AND 7 ARE THOUGHT TO BE
ZOONOTIC INFECTIONS.
THE HEPATITIS E VIRUS HAS A
CAPSID COMPRISED OF 180 COPIES
OF THE CAPSID PROTEINS AND TWO
PRART CAL HAVE BEEN IDENTIFIED.
ONE IS A QUASI-ENVELOPE SPECIES
WRAPPED IN A HOST LIPID ENVELOPE
AND NOT ENVELOPE VIRUS AND THE
ENVELOPE VIRUS IS THOUGHT TO BE
RESISTANT AGAINST THE VIRAL
CAPSID PROTEIN AND MAY BE
IMPORTANT FOR THE TROPISM AND
THE NON-VIRAL VIRUS IS THOUGHT
TO BE THE MORE INFECTIOUS ONE
AND THE ONE RESPONSIBLE FOR
TRANSMITTING THE INFECTION.
AND THE GENOME AS SHOWN IN THE
CARTOON IS A POSITIVE SENSE
SINGLE STRAND RNA OF
APPROXIMATELY 7.2 KB IN LINK AND
THE IT THERE'S A POLY ADENY
LATED END AND THERE'S A LARGE
PROTEIN OF 1700 AMINO ACIDS
IMPORTANT FOR VIRAL REPLICATION.
RF2 AND 3 COME FROM AN RNA AND
THERE'S A SHELL, MIDDLE AND
PROTRUDING DOMAIN AND THOUGHT TO
BE A SITE FOR A NEUTRALIZING
ANTIBODY OR 3 SEEMS TO BE
IMPORTANT FOR VIRAL ASSEMBLY AND
SECRETION OF THE VIRUS AND THE
FOURTH IDENTIFIED IN GEOTYPE 1
INFECTION AND A REPLICATION
ENHANCER MAY BE RELEVANT FOR THE
DISEASE MEDIATED OR CAUSED BY
HEPATITIS E VIRUS TYPE 1.
SO HOW DOES THE VIRUS REPLICATE?
THAT IS SHOWN IN THE CARTOON.
THE VIRUS CAUSES AND INFECTS
REPLICATES WITHIN HE PAPATOCYTE
AND INTERACTED WITH ANOTHER
SURFACE RECEPTOR AND THROUGH A
MEDIATED PROCESS.
AND ENCODES THE ORF1 PROTEIN FOR
A SUB GENOMIC NEGATIVE STRAND
RNA WHICH SERVES AS A TEMPLATE
FOR TRANSCRIPTION AND
TRANSLATION OF THE OTHER TWO
PROTEINS THE ORF2 AND 3 AND THE
CAPSID PROTEINS SHOWN BY THE
LIGHT BLUE TRIANGLES GOES TO THE
RETICULUM WHERE VIRAL ASSEMBLY
HAPPENS WITH THE POSITIVE SENSE
RNA STRAND.
THIS WORKS ITS WAY THROUGH THE
SECRETORY PROCESS OF THE CELL
AND REQUIRES THE ORF3 PROTEIN
FOR THIS PURPOSE AND BECOMES AN
ENVELOPE WITH HOST LIPIDS AND
SECRETED THROUGH AN EXOSOMAL
PATHWAY AND IT CONTAINS HOST
LIPIDS AS WELL AS OPEN READING
FRAME THREE.
AND IT'S THEN SECRETED INTO
WHERE THE BILE REMOVES THE HOST
LIPIDS AND THE NON-ENVELOPE
VIRUS GOES DOWN THE
GASTROINTESTINAL TRACT AND
SECRETED IN STOOL AND COMPLETES
ITS LIFE CYCLE AND 4 HAS BEEN
IDENTIFIED AS A HYPERENDEMIC,
DISTINCTIVE AND SPORE -- SPO
SPORATIC AND THERE'S ASIA AND
MEXICO AND ENDEMIC REGIONS SHOW
CHINA, PARTS OF JAPAN AND THE
MIDDLE EAST AND ENDEMIC REGIONS
ARE ASSOCIATED WITH LARGE WATER
BORN OUTBREAKS TYPICALLY DUE TO
HEPATITIS GENOTYPE 1 AND 2.
THERE'S A DISTINCT ZONE SHOWN IN
GREEN AND IT'S DIFFERENT FROM
OTHER REGIONS OF THE WORLD AND
DUE TO INFECTION WITH A SUBTYPE
OF GENOTYPE 1 AND THEN FOR THE
REST OF THE WORLD WHICH IS
ESSENTIALLY MOSTLY DEVELOPED
REGIONS BUT ALSO SOME EMERGING
COUNTRIES DUE TO SPORADIC OR
LOCALLY ACQUIRED HEPATITIS E
ASSOCIATED WITH INFECTION AND
JUNO TYPE 3 AND 4 WE'LL TALK
ABOUT FURTHER IN THE TALK.
IT'S BEEN DIFFICULT TO DETERMINE
THE TRUE PREVALENCE OF HEPATITIS
E GLOBALLY BECAUSE OF THE
SPECIFICITY OF THE ASSAYS AND
PAUCITY FROM THE AMERICAS AND
THIS IS DATA FROM META-ANALYSIS
SHOWING THE PREVALENCE BASED ON
IGG, IGM AND HEV RNA AND THE
HIGHEST PREVALENCE IS IN AFRICA.
THE HIGHEST PREVALENCE IS IN
AFRICA AND ASIA FOLLOWED BY
SOUTH AMERICA AND OCEANA AND THE
PREVALENCE OF HEV RNA VERY LOW
BUT WE SHOULD INTERPRET SOME
DATA WITH CAUTION BECAUSE OF THE
PAUCITY OF DATA PARTICULARLY
FROM AFRICA AND THE AMERICAS.
THIS SLIDE SHOWS THE GLOBAL
DISTRIBUTION OF THE FOUR MAJOR
PHENOTYPES THAT INFECT HUMANS, 1
THROUGH 4.
1 IN RED AND 2 IN BLUE AND 3 IN
YELLOW AND 4 IN BROWN.
YOU SEE THE GLOBAL DISTRIBUTION
OF THE GENOTYPES ESSENTIALLY
MIRRORS OF THAT THE DIFFERENT
ZONALITY OF HEPATITIS D ON THE
PREACHES SLIDE.
SO HEPATITIS GEOTYPES 1 AND 2
ARE ASSOCIATED WITH LARGE
WATERBORNE OUTBREAKS IN THE
REGIONS SHOWN HERE AND GENOTYPE
3 IS ASSOCIATED WITH LOCALLY
ACQUIRED HEPATITIS E.
AND GENOTYPE 4 IS SEEN IN CHINA
AND JAPAN.
TRANSMISSION AND HYPER ENDEMIC
AND ENDEMIC REGIONS IS THROUGH
THE FECAL-ORAL ROUTE AND WATER
AND PERSON TO PERSON
TRANSMISSION NOT THE COMMON
ROUTE OF TRANSMISSION.
BY TRANSMISSION OF SPORADIC OR
HEPATITIS B IS THOUGHT TO BE
ZOONOTIC AND TRANSMISSION IS
PRIMARILY THROUGH DIRECT CONTACT
WITH AN INFECTED ANIMAL SUCH AS
A PERSON WITH OCCUPATIONAL
EXPOSURE SUCH AS VETS, FARMERS,
FARM WORKERS AND INDIRECT
EXPOSURE TO ANIMAL FECES FROM
CONTAMINATED WATER AND THE OTHER
IS THROUGH CONSUMPTION MUCH
INFECTED MEAT IMPROPERLY
PREPARED AND MEAT FROM PIGS,
WILD BORE OR DEER AND THERE'S
BLOOD TRANSMISSION THROUGH BLOOD
PRODUCTS FROM MOTHER TO INFANT
OR VERTICAL TRANSMISSION AND
THROUGH OCCUPATIONAL EXPOSURE.
AS MENTIONED ALSO WITH ENDEMIC
FORMS FROM PERSON TO PERSON IS
NOT COMMON.
THIS SHOWS THE COURSE OF ACUTE
HEPATITIS E AND THE MAJORITY OF
CASES HEPATITIS E PRESENTS AS A
SYMPTOMATIC INFECTION AND NOT
RECOGNIZED BUT IN 30% OF
PATIENTS THE CLASSIC
PRESENTATION ENSUES AND THERE'S
A PRODROMAL AND CONVALESCENT
PHASE HAS BEEN IDENTIFIED AND
ONE LASTED BY TWO TO SIX WEEKS
CHARACTERIZED BY NON SPECIFIC
SYMPTOMS SUCH AS MALAISE AND
THERE'S ENTERIC PHASE WHERE
JUANDICE IS PRESENT AND DARK
URINE AND CAN LAST FROM A COUPLE
DAYS TO SEVERAL WEEKS AND
FOLLOWED BY THE CONVALESCENT
PHASE WHERE RECOVERY ENSUES IN
ALMOST ALL CASES AND ALT LEVELS
RETURN TO NORMAL AND JUANDICE
RESOLVES.
LOOKING AT THE SEROLOGIC
PROFILE, IGM IS DETECTED IN
ALMOST EVERYONE AT THE TIME OF
PRESENTATION OF JUANDICE AND CAN
BE RELIABLY DETECTED IN MOST
INDIVIDUALS WITHIN TWO WEEKS OF
INFECTION.
IT RAPIDLY RISES AND REMAINS
DETECTABLE UP TO FIVE MONTHS.
IGG ANTIBODY FOLLOWS CLOSELY THE
COURSE OF IGM BUT REMAINS
ELEVATED UP TO 14 YEARS AND IS A
MARKER OF PRIOR EXPOSURE TO THE
VIRUS.
HEPATITIS E VIRUS RNA AND VIRUS
DETECT IN STOOL CAN BE DETECTED
DURING THE INCUBATION OF
PRODOMAL PHASE AND REMAINS
POSITIVE FOUR TO SIX WEEKS
RESPECTIVELY FOR EACH OF THE
DIFFERENT PARAMETERS.
THERE'S DIAGNOSIS FIRST THE
INDEX OF SUSPICION AND THE FIRST
TEST SHOULD BE FOR ANTI-HIV AGM
AND IF POSITIVE IT SHOWS RECENT
OR ACTIVE INFECTION BUT SHOULD
BE CONFIRMED BY TESTING FOR
HEPATITIS E RNA.
IF BOTH ARE POSITIVE THIS
INDICATES RECENT AND ACTIVE
INFECTION.
NOW, IF IMMUNOCOMPROMISED
INDIVIDUALS TESTING SHOULD BEGIN
WITH ANTI-HIV IGM BUT A MAJORITY
MAY BE NEGATIVE AND IT SHOULD BE
MANDATORY TO TEST FOR IGV RNA
AND IF PRESENT INDICATES RECENT
INFECTION.
IN THE PAST THE AVAILABILITY OF
TESTING FOR THE RNA WAS
DIFFICULT TO COME ABOUT.
THIS HAS NOW CHANGED AND THESE
TESTS ARE AVAILABLE AT MOST
COMMERCIAL LABORATORIES.
HERE AT THE NIH PATRICIA'S
FOSSI'S LAB STILL TESTS FOR IT
AND WHEN SHOULD ONE TEST FOR
HEPATITIS E VIRUS RNA IN
SITUATIONS WHERE PATIENTS HAVE A
POOR IGM RESPONSE IT'S
RECOMMENDED TO ORDER AN HEV00
AND MANDATORY FOR CHRONIC
INFECTION AND PRIOR TO JORG
ORRINGAN TRANSPLANTATION.
AND NEEDED FOR BLOOD TRANSFUSION
AND I'LL GET TO THIS LATER IN
THE TALK.
OF COURSE TO EVALUATE THE
RESPONSE TO ANTI-VIRAL DRUG
THERAPY.
NOW, I WANTED TO SAY A FEW WORDS
ABOUT DIAGNOSTIC TEST FOR
HEPATITIS E BECAUSE THERE ARE A
LOT OF ISSUES CURRENTLY WITH THE
CURRENT ASSAYS.
MOST THE DIAGNOSTIC ASSAYS RIGHT
NOW RELY ON RECOMBINANT ASSAYS
AND THEY'RE HIGHLY VARIABLE.
THIS LEADS TO A LOT OF
CONSTERNATION WITH BEING ABLE TO
DETERMINE WHAT THE TRUE
PREVALENCE OF HEPATITIS E IS
GLOBALLY AND THIS WAS
ILLUSTRATED IN THE STUDY BY
DR. PURCELL WHERE THEY TESTED A
PANEL FOR HEPATITIS E USING 12
ASSAYS AND YOU CAN SEE AMONG
PRIOR REACTIVE TEST SAMPLES BY
TWO OR MORE TESTS, YOU CAN SEE A
WIDE VARIATION IN POSITIVITY
THERE FROM A LOW OF 6% TO A HIGH
OF 100% AND YOU CAN SEE THE
NUMBER THAT TESTED POSITIVE
RANGE FROM 4 TO 71% AND AMONG 39
SAMPLES PREVIOUSLY TESTED
NEGATIVE BY TWO OR MORE ASSAYS,
THE DETECTION RATE RANGED FROM 0
TO 31%.
SO THE OVER ALL CONCORDANCE
RANGED FROM 49 TO 94%.
THIS HIGHLIGHTS THE ISSUE WITH
THE CURRENT DIAGNOSTIC ASSAYS.
THIS PARTICULARLY RELEVANT IN
LOW ENDEMIC REGIONS.
I WANTED TO BRING THIS TO YOUR
ATTENTION AND WORD OF CAUTION
HOW WE INTERPRET THE RESULTS OF
PREVALENCE STUDIES FROM LOW
ENDEMIC AREAS.
IT'S ALL OVER THE MAP.
SO, I WANT TO TURN TO THE
CLINICAL FEATURES OF HEPATITIS E
AND THIS SHOWS THE COMPARISON OF
CLINICAL AND EPIDEMIOLOGIC FEE
TIRES OF HEPATITIS E AND THEY'RE
QUITE DISTINCTIVE AND DIFFERENT
AND FROM OTHER FORMS OF VIRAL
HEPATITIS.
ONE CAN DESCRIBE THEM AS TWO
DIFFERENT DISEASES.
THE DISTRIBUTION IS PRIMARILY
THOSE 15 TO 40 YEARS OLD WHERE
LOCALLY ACQUIRED AUTOCHTHONOUS
IS IN DIFFERENT FORM AND THERE'S
MALE DOMINANCE IN LOCALLY
ACQUIRED HAEMENT
AND THE SEASONALITY WITH THE
FORMS AND LOC ALY
-- LOCALLY ACQUIRED HEPATITIS E
AND THE ONLY RESERVOIR IS HUMAN
WHERE AUTOCHTHONOUS HEPATITIS E
THERE'S A PREVALENCE THROUGHOUT
LIFE AND AUTOCHTHONOUS HEPATITIS
E MY PRESENT WITH NEUROLOGICAL
COMPLICATIONS.
SO THE CLINICAL PRESENTATION OF
LOCALLY ACQUIRED AUTOCHTHONOUS
HEPATITIS E IS SHOWN HERE AND
FOR MOST IT'S AN ASYMPTOMATIC
INFECTION AND A SMALLER
PROPORTION PRESENT WITH
INFECTION THAT GOES UNRECOGNIZED
AND A SMALL PROPORTION OF
PATIENTS PRESENT WITH
SYMPTOMATIC CLASSIC HEPATITIS
WITH JUANDICE.
I WANTED TO HIGHLIGHT ONE NEEDS
TO HAVE A HIGH SUSPICION FOR
HEPATITIS E BECAUSE THERE'S A
VARIABLE PRESENTATION THAT
INCLUDES ACUTE HEPATITIS AND
ACUTE AND CHRONIC LIVER FAILURE
MAY PRESENT AS A DRUG INDUCED
LIVER INJURY WITH SYMPTOMS
WITHOUT LIVER FEATURES AND THEN
AS MISCELLANEOUS SYNDROME
INCLUDING THAT OF A GLOBULAR
NEPHRITIS.
YOU HAVE TO HAVE YOUR CLINICAL
CLINICIAN HAT ON TO SOMETIMES
DIAGNOSE HEPATITIS E AND THIS
WILL BE IN SEVERAL STUDIES I'LL
SHARE NOW.
ONE STUDY SHOWED THE LIVER
FAILURE ASSOCIATED WITH HIGH
MORTALITY AND THIS WAS CONDUCTED
IN INDIA LOOKING AT 107 CIR
OTICS SUGGESTING IT MAY BE
PREDISPOSED TO ACQUIRING
HEPATITIS E VIRUS INFECTION.
AND GROUP 3 WAS CIR OTIC WITH A
STABLE DISEASE AND LOOKING AT
THE GREEN LINE THEY HAVE RAPID
DECOMPOSITION ANDRHOTIC WITH A
STABLE DISEASE AND LOOKING AT
THE GREEN LINE THEY HAVE RAPID
DECOMPOSITION AND IN COMPARISON
THOSE WITH CIRRHOSIS WITHOUT
DECOMPENSATION VIRAL RNA WAS
PRESENT IN ONLY 10% AND THEIR
SURVIVAL WAS MORE THAN 90% AT
ONE YEAR.
IN CONTRAST, HEPATITIS D IS
RARELY ASSOCIATED WITH ACUTE AND
CHRONIC LIVER FAILURE IN THE
U.S. AND THIS IS DATA FROM THE
LIVER UNIT CONDUCTED BY ONE OF
THE FELLOWS AND THEY LOOKED AT
PATIENTS WHO HAD PARTICIPATED IN
THE TRIAL LOOKING AT LOW DOSE
PEGINTERFERON AND TREATED FOR
FOUR YEARS.
THERE WERE 314 PATIENTS WHO
EXPERIENCED HEPATIC
DECOMPENSATION AND 89 PATIENTS
WEREFIDE WITH RAPID
DECOMPENSATION WITHIN 24 WEEK
PERIOD AND IDENTIFIED 267
CONTROLS WITHOUT DECOMPENSATION
AND THEY WERE ALL TESTED FOR
HEPATITIS E.
I GG, IGM AND RNA.
YOU CAN SEE THE PREVALENCE OF
IGG WAS SIMILAR BETWEEN CASES
AND CONTROLS SIMILAR TO THE
PREVALENCE OF THE
U.S. POPULATION AT THE TIME THE
STUDY WAS CONDUCTED.
AND THE PREVALENCE OF IGM WAS
BETWEEN CASES OF CONTROLS AND NO
PATIENTS HAVE HIV RNA
HIGHLIGHTING AT LEAST IN
NON-ENDEMIC AREA IT'S NOT A
CAUSE OF ACUTE AND CHRONIC LIVER
FAILURE AND ANOTHER STUD AGREE
FROM THE U.S.
THIS ONE FROM THE ACUTE LIVER
INJURY CONSORTIUM ANOTHER LARGE
NIH CONSORTIUM OF OVER 600
PATIENTS WERE EFFTESTED WITH AC
LIVER FAILURE AND ONLY 10%
TESTED POSITIVE FOR IGG AND ONE
WAS FOUND TO BE RNA POSITIVE AND
IDENTIFIED AS HAVING GENOTYPE 3
INFECTION AND ONE HAD DETECT AND
HEPATITIS E ANTIGEN HIGHLIGHTING
IT'S NOT A MAJOR CAUSE OF ACUTE
LIVER FAILURE COMPARED TO THE
DATA FROM EPIDEMIC AREAS.
HEPATITIS E MAY MASQUERADE AS A
DRUG-INDUCED LIVER INJURY.
THIS IS DATA FROM A LARGE NIH
FUNDED NETWORK LOOKING AT OVER
300 PATIENTS AND DILI AND ONLY A
MINORITY WERE IGM POSITIVE AND
ONLY FOUR WERE RNA POSITIVE AND
THEY REASSESSED AND IT WAS
EVIDENT SEVEN OF THESE HEPATITIS
E WAS LIKELY THE CAUSE AND THE
CASES WERE MISDIAGNOSED AND THE
OTHER TWO WERE LIKELY TO HAVE
HEPATITIS E AND NOT A
DRUG-INDUCED LIVER INJURY AND IT
CAN PRESENT WITH AN INITIAL
PRESENTATION THOUGH A LOT OF THE
DATA COMES FROM SINGLE CASE
REPORTS OR SMALL CASE SERIES SO
IT'S BEEN DIFFICULT TO ESTABLISH
A CAUSALITY.
HOWEVER, FOR THE NEUROLOGICAL
COMPLICATIONS, THEY'RE MUCH
LARGER SERIES AND A GREATER
BURDEN OF DATA WHICH DOES
SUGGEST THERE MIGHT BE A
CAUSALITY AS LISTED THERE.
I WANTED TO TALK ABOUT PREGNANCY
WHERE IT CAN REACH AS HIGH AS
33%.
THERE'S A HIGHER RATE OF ACUTE
LIVER FAILURE IN PREGNANT WOMEN
AND THE MECHANISMS AREN'T CLEAR.
CLINICAL AND ANIMAL DATA TO
SUGGEST HEPATITIS E CAN INFECT
THE PLACENTA AND CAUSE INJURY
INCLUDING FIBROSIS AND FIBROSIS
OF THE CORD AND THERE'S EVIDENCE
OF VERTICAL TRANSMISSION TO THE
FETUS WHICH CAN CAUSE SEVERE
NEONATAL HEPATITIS AND THE
IMMUNE DYSFUNCTION DURING
PREGNANCY CAN LEAD TO HIGHER
VIRAL REPLICATION AND LEAD TO
WORSE OUTCOMES.
THE TRUE CAUSE FOR THE WORSE
DISEASE IN PREGNANT WOMEN NOT
CLEAR.
AND THIS IS AN AREA OF ACTIVE
RESEARCH.
FOLLOWING THE DISCOVERY IT WAS
LONG THOUGHT OR BELIEVED
HEPATITIS E WAS A SELF-LIMITING
HEPATITIS SIMILAR TO HEPATITIS A
AND IN THE LATE 1980s, CASE
REPORTS BEGAN TO EMERGE OF VIRUS
RNA IN DELIVER TRANSPLANT
RECIPIENTS AND IT'S NOW WELL
DOCUMENTED HEPATITIS E CAN CAUSE
A CHRONIC INFECTION BUT OCCURS
ALMOST EXCLUSIVELY AMONG
IMMUNOCOMPROMISED PERSONS AND
SOLID ORGAN TRANSPLANT
RECIPIENTS, PATIENTS RECEIVING
CANCER THERAPY AND HIV INFECTED
PERSONS.
THE PREVALENCE IS 1 TO 2% AND
ONLY BEEN REPORTED WITH GENOTYPE
3 INFECTION.
ABOUT 10% OF PATIENTS CAN
PROGRESS TO CIRRHOSIS AND THE
SOURCE OF INFECTION IS OFTEN
UNKNOWN.
SHOWN HERE IS THE PREVALENCE OF
HEPATITIS E IN THE SOLID ORGAN
TRANSPLANT POPULATION.
IT'S ESTIMATED USING IGG IT'S
ABOUT 20% AND THAT'S SIMILAR TO
THE GENERAL POPULATION.
AND IT VARIES BY THE
TRANSPLANTED ORGAN BEING HIGHEST
IN LIVER FOLLOWED BY KIDNEY,
HEART AND LUNG AND THE RATE OF
CHRONIC INFECTION IS LOW.
IT'S ABOUT .5% TO 1.5% AND
IMPORTANT TO RECOGNIZE
RE-INFECTION MAY RE-OCCUR.
CO-INFECTION WITH HEPATITIS E
HAS BEEN DESCRIBED NOW.
FIRST CASE REPORT WAS PUBLISHED
IN THE NEW ENGLAND JOURNAL AND
THE INCIDENTS IN THE POPULATION
IS LOW FROM 0 TO 9% AND RELATED
TO GENOTYPE 3 INFECTION.
A LOW CD4 COUNT IS THE ONLY RISK
FACTOR IDENTIFIED IN THIS
POPULATION AND ONE CASE REPORT
WITH PROGRESSION WITH CIRRHOSIS.
THIS SHOWS A CARTOON WHICH IS A
MANAGEMENT ALGORITHM FOR
PATIENTS WITH CHRONIC HEPATITIS
E INFECTION.
AS I MENTIONED IN THE VAST
MAJORITY OF INDIVIDUALS WITH
ACUTE HEPATITIS E THERE'S GOING
TO BE SPONTANEOUS RESOLUTION
WITH CLEARANCE OF THE VIRAL RNA.
HOWEVER, THERE'S A SMALL
PERCENTAGE OF PATIENTS WHERE THE
RNA WILL PERSIST BEYOND SIX
MONTHS AND THIS IS THE
DEFINITION OF CHRONIC INFECTION.
THE FIRST IS APPROACH IF
RECEIVING IMMUNOEXPRESSIVE --
IMMUNOSUPPRESSIVE CASES AND CAN
CLEAR AND IF NOT MEDICATION
LEADING TO VIRAL CLEARANCE FOR
THREE-QUARTERS OF PATIENTS AND
THE REGIMENT IS EMPIRICAL AND WE
DON'T KNOW WHAT THE OPTIMAL DOSE
IS FOR TREATING HEPATITIS E JUST
BECAUSE THE CHRONIC INFECTION IS
SO RARE IT'S DIFFICULT TO DO
LARGE CONTROLLED STUDIES.
IF THE VIRUS PERSISTS AFTER.
THERE'S TWO OPTIONS, ONE TO
CONTINUE WITH THE MEDICATION FOR
AN ADDITIONAL TWO MONTHS OR FOR
LIVER TRANSPLANT RECIPIENTS TO
RECOMMEND PEGINTERFERON AND IT'S
EFFECTIVE IN 34% OF PATIENTS.
PEGINTERFERON IS CONTRAINDICATED
IN OTHER TRANSPLANT RECIPIENTS
BECAUSE OF HIGH RISK OF ORGAN
REJECTION.
WHAT ABOUT PREVENTION.
FOR AUTOCHTHONOUS HEPATITIS
ISOLATION OF ANIMALS AND
MONITORING WASTE RUNOFF BUT NOT
WIDELY ADOPTED AND FOR
INDIVIDUALS THE ONE SINGLE THING
YOU CAN DO TO TRY TO PREVENT
HEPATITIS E INFECTION IS AVOID
CONSUMPTION OF UNDER COOKED MEAT
PARTICULARLY PORK OR GAME AND IT
SHOULD BE HEATED TO 160 DEGREES
FOR AT LATEST 20 MINUTES BEFORE
CONSUMPTION AND ONE SHOULD AVOID
CONSUMPTION OF RAW SHELLFISH
ESPECIALLY IF IMMUNOCOMPROMISED
AND THIS HAS BEEN IMPLEMENTED IN
A FEW WESTERN COUNTRIES.
THE PREVALENCE OF HEPATITIS E
RNA RANGES THERE 1 TO 4,000
DONORS AND 11 EUROPEAN COUNTRIES
RECOMMEND MINI POOL SCREENING
FOR HEPATITIS E.
HO
HOWEVER, THIS IS NOT YET ADOPTED
IN THE UNITED STATES.
ONE STUDY CONDUCTED HERE AT THE
NIH HARVEY ALTER SCREENED FOR
HEPATITIS E AND FOUND A
PREVALENCE OF 22% CORRESPONDING
TO THE PREVALENCE OF HEPATITIS E
IN THE GENERAL U.S. POPULATION
AT THE TIME AND NONE WERE FOUND
TO BE HEPATITIS E RNA BUT
THERE'S DEBATE GOING ON WHETHER
THE U.S. SHOULD ADOPT SCREENING
FOR HEPATITIS E BUT PART OF THE
REASON IT HASN'T YET IS BECAUSE
OF THE PRESUMED LOW PREVALENCE
OF HEPATITIS E IN THE U.S.
FOR EPIDEMIC HEPATITIS E TO
IMPROVE SANITATION AND AVOID
CONTAMINATED WATER WE NOW HAVE A
SAFE VACCINE AVAILABLE.
THERE'S THREE RECOMBINANT
HEPATITIS E VACCINES DEVELOPED.
ALL DERIVED FROM THE PROTEIN AND
CLINICAL EFFICACY HAS BEEN
DEMONSTRATED WITH ALL THREE
PRODUCTS.
THE FIRST WAS CO-JOINTLY
DEVELOPED BY GLAXOSMITHKLINE AND
NIAID AND THE VACCINE DOESN'T GO
FURTHER BECAUSE OF ECONOMIC
CONSIDERATIONS AND ANOTHER WAS A
VACCINE DEVELOPED IN CHINA AND
DEMONSTRATED EFFICACY IN A PHASE
1 TRIAL BUT DIDN'T MOVE FORWARD
BECAUSE OF ECONOMIC
CONSIDERATIONS AND THE THIRD
VACCINE HEV-239 WAS DEMONSTRATE
AND CURRENTLY LICENSED IN CHINA
AND PAKISTAN.
THIS IS A DATA FROM THE
RANDOMIZED TRIAL THAT LED TO THE
APPROVAL OF THIS VACCINE THE
VACCINE WAS TESTED IN OVER 100
ADULTS AND PATIENT RANDOMIZED TO
RECEIVE THE MEDICATION OR
PLACEBO AND HEPATITIS B VIRUS
AND THE PRIMARY END POINT WAS
AFTER THE LAST DOSE OF THE
VACCINE IN THE PROTOCOL
ANALYSIS, 15 CASES OF HEPATITIS
C OCCURRED AND THE INTENTION TO
TREAT ANALYSIS THERE WERE 22
CASES AND 21 OCCURRED IN THE
PLACEBO GROUP COMPARED TO ONE IN
THE VACCINE GROUP FOR A VACCINE
EFFICACY OF 95%.
THIS FOLLOW UP WAS EXTENDED FOR
4.5 YEARS AND 60 CASES OF
HEPATITIS E WERE IDENTIFIED.
SEVEN IN THE VACCINE GROUP AND
53 IN THE CONTROL GROUP FOR AN
OVER ALL VACCINE EFFICACY OF 87%
OVER THE 4.5 YEAR FOLLOW UP.
AND 87% OF THOSE WHO RECEIVED
THREE DOSES OF THE VACCINE
MAINTAINED ANTIBODY UP TO 4.5
YEARS LATER INDICATING THE
VACCINE IS VERY DURABLE.
ONE WOULD ASK WHY ISN'T THE
VACCINE BEING USE MORE
WIDESPREAD.
THERE'S A NUMBER OF BARRIERS TO
VACCINE USE.
FIRST IS THE LIMITED AWARENESS
REGARDING HEPATITIS E AND THE
AVAILABLE VACCINE AMONG
REGULATORS, POLICY MAKERS AND
COMMUNITIES THAT ARE PRONE TO
LARGE OUTBREAKS.
THERE'S ALSO LIMITED DATA ON
VACCINE EFFICACY ONLY ONE STUDY
FROM AN OUTBREAK DATA AND
THERE'S LIMITED INFORMATION ON
PREGNANT WOMEN AND YOUNGER AGE
GROUPS AND THE LAST THREE
FACTORS HAVE BEEN THE MAJOR
REASONS W.H.O. HASN'T BEEN A
GREATER PROPONENT OF
RECOMMENDING MORE WIDESPREAD USE
OF THE VACCINE AND THERE'S
UNCERTAINTY ABOUT THE VACCINE
SUPPLY.
TO SUMMARIZE FOR YOU IN RESOURCE
LIMITED AREAS HEPATITIS E IS
PRIMARILY WATERBORNE WITH
HEPATITIS RELATED TO INFECTION
WITH PHENOTYPES 1 AND 2 AND IN
HIGH INCOME COUNTRIES IT'S
CONSIDERED A ZOONOTIC INFECTION
CAUSING ACUTE AND CHRONIC
INFECTION AND CHRONIC INFECTION
IS ONLY ASSOCIATED WITH GENOTYPE
3 NEVER 1 OR 2.
AND A WANTED TO HIGHLIGHT A FEW
UNRESOLVED ISSUES I THINK ARE
AREAS FOR FURTHER INVESTIGATION
WE DON'T KNOW HOW TO EXPLAIN THE
HIGH MORTALITY IN PREGNANT WOMEN
OR WHAT ACCOUNTS FOR THE
MANIFESTATIONS OF GENOTYPE 3 AND
DON'T KNOW THE OPTIMAL THERAPY
AND MORE EFFECTIVE THERAPIES
WOULD BE DESIRABLE.
THERE'S DEBATE GOING ON WHETHER
THE BLOOD SUPPLY SHOULD BE
SCREENED.
AND THIS PARTLY RELATED TO WHAT
THE PREVALENCE IS IN YOUR
PARTICULAR REGION.
WE NEED BETTER DIAGNOSTIC TESTS
AS HIGHLIGHTED AND NEEDS TO BE
MORE STUDIES OF VACCINE EFFICACY
IN OTHER REGIONS AND OTHER
POPULATIONS AN TO DETERMINE
WHETHER THERE'S CROSS-PROTECTION
BETWEEN THE VACCINE OR
GENOTYPES.
SO I THINK I'LL STOP IT THERE
AND HAPPY TO TAKE ANY QUESTIONS.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
>> THANK YOU VERY MUCH.
THERE'S A MICROPHONE IN THE
AISLE THERE.
BASED ON YOUR RESEARCH WHAT
GUIDELINES WOULD YOU RECOMMEND
FOR THE GENERAL PUBLIC FOR
TESTING AND VACCINATION?
>> I THINK IT'S RELATIVELY
STRAIGHTFORWARD.
TO REPEAT THE QUESTION, WHAT GID
LINES WOULD BE RECOMMENDED IF
THE CURRENT GUIDELINES ARE
SUBOPTIMAL.
EVERYONE IN HEPATITIS B SHOULD
BE CHECKED FOR HEPATITIS E ONCE
AND VACCINATION HEPATITIS B
SHOULD BE UNIVERSAL.
VERY EASY.
>> IT'S ALSO BEEN ASKED WHETHER
SAMPLES OF THE BLOOD BANK FROM
YEARS GONE BY HAVE BEEN TESTED
TO GIVE SOME CLUE AS TO HOW LONG
THEY'VE BEEN IN THE CIRCULATION
AND NOT PREVIOUSLY RECOGNIZED.
DO YOU WANT TO COMMENT?
>> I MENTIONED HOW HARVEY ALTER
LOOKED AT 1,000 BLOOD DONOR
SAMPLES AND THE PREVALENCE OF
ANTIBODY TO HEPATITIS B, IGG WAS
20% BUT NONE WERE FOUND TO BE
HEPATITIS B RNA AND THAT FIGURE
RESEMBLES THE PREVALENCE IN THE
U.S. GENERAL POPULATION BASED ON
THE NHANES STUDY DONE IN 2010
AROUND THE SAME TIME.
>> TO ADDRESS THE HEPATITIS B IN
TERMS OF SUBTEXT, HOW LONG HAS
IT BEEN IN CIRCULATION?
IT'S INTERESTING.
IF YOU'RE GOING TO ISOLATED
POPULATIONS IN THE AMAZON AND
GLOBALLY, POPULATIONS THAT HAVE
HAD NO CONTACT FOR THOUSANDS OF
YEARS WITH OTHER POPULATIONS,
YOU FIND HEPATITIS B AND D.
SO HEPATITIS B HAS BEEN AROUND
AS LONG AS HUMANS HAVE AND
HEPATITIS D GOES BACK PRETTY
FAR.
>> WHAT DO WE KNOW ABOUT
RETENTION RATES --
>> WELL, I WANTED TO ASK A
COUPLE QUESTIONS.
FIRST, TO BOTH PRESENTERS, WHAT
IS YOUR SPECULATION WITH REGARD
TO ARE THERE OTHER ISSUES NOW
GONE TO BE DISCOVERED AND WE'VE
GONE THROUGH FIVE LETTERS OF THE
ALPHABET AND THE SIXTH IS
PERHAPS BECKONING FOR DISCOVERY.
AND WHAT HAPPENED TO BERIANI WHO
DEMONSTRATE THE LIKELY
INFECTIOUS AGENT FOR HEPATITIS
D.
I HOPE HE SURVIVED.
>> HE SURVIVED.
HE WAS ACTUALLY QUITE SICK BUT
HAD A SELF-LIMITING HEPATITIS.
>> HE LOVED TELLING THE STORY
AND ONE OF THE THINGS HE TOLD US
WAS HE CHOSE CHOCOLATE ICE CREAM
SO HE WOULDN'T HAVE TO SEE WHAT
HE WAS EATING AND HE WAS --
THERE WERE AMUSING THINGS ABOUT
HIM.
FOR MANY REASONS HE WAS A HUGE
GUY WITH A LOT OF CHARISMA AND
PERSONALITY.
DO YOU WANT IT TAKE THE NEXT
QUESTION?
>> THE FIRST QUESTION WAS WERE
THERE OTHER VIRUSES WAITING TO
BE DISCOVERED AND THERE IS
HEPATITIS G AND NONE
CONVINCINGLY SHOWN TO BE RELATED
TO TRANSFUSION RELATED
HEPATITIS.
THEY JUST OCCUR IN THE
POPULATION BUT PROBABLY DON'T
CAUSE ANY DISEASE.
AS A TESTAMENT THE TRANSFUSION
OF HEPATITIS IS EXCEEDINGLY RARE
AND IF THERE'S VIRUSES TO BE
IDENTIFIED THEY WON'T BE A
SIGNIFICANT COURSE FOR
TRANSFUSION RELATED HEPATITIS.
MAYBE THEO WANTS TO ADD.
>> THERE WAS HEPATITIS F BUT IT
TURNED OUT NOT TO BE TRUE.
>> THAT WAS GOING TO BE MY NEXT
QUESTION.
>> IT'S BY THE FRENCH AND TURNED
OUT NOT TO BE THE CASE AND THE
VARIOUS WAS TRANSMITTED FROM
GENERAL SURGEON BUT IT WAS A
PRIMATE VIRUS GBV.
I AGREE WITH MARC BUT THERE'S
ONE PIECE OF DATA WHICH LOOKED
AT AN OUTBREAK ON AN ISLAND OFF
THE COAST OF INDIA COULD NOT
IDENTIFY THE NON-HEPATITIS VIRUS
AND SEEMED TO SPREAD CONSISTENT
WITH THE HEPATITIS VIRUS AND
MAYBE SOME ARE LOOKING TO BE
DISCOVERED.
>> MAYBE SOMEONE IN THE FUTURE.
OR THE ROOM.
YOU SAID THE F WAS FROM A FRENCH
INVESTIGATOR AND THE G A GERMAN.
>> YES.
>> THAT'S INTERESTING.
>> WE STILL DON'T KNOW THE CAUSE
OF HEPATITIS.
>> THERE WAS AN OUTBREAK OF
HEPATITIS TWO YEARS AGO THAT
OCCURRED PRIMARILY IN CHILDREN
AND THERE WERE TWO CHARGE
COHORTS DESCRIBED.
BOTH FROM BIRMINGHAM, ALABAMA
AND ENGLAND.
THERE ARE MORE CASES BEING
IDENTIFIED.
WE HAVE A QUESTION WITH OTHER
HEPATOVIRUSES HAVE THE CAPACITY
TO ACCEPT HEPATITIS D.
>> ARE THERE OTHER VIRUSES THAT
CAN TRANSMIT HEPATITIS D.
IT DOESN'T SEEM TO BE THE CASE
AND THERE IS A CASE LOOKING AT
SC
SCHOGREN'S SYNDROME.
>> WE HAVE A QUESTION AS TO WHAT
DO WE KNOW ABOUT THE MUTATION
RATE OF THESE VIRUSES?
>> IT HAS A ROD-LIKE STRUCTURE.
IT'S ALMOST LIKE A DNA MOLECULE
THOUGH IT'S RNA AND THERE'S
EXTENSIVE BASE PAIRING AND IF
THERE IS ONE THAT NEEDS TO BE
COMPENSATED ON THE OTHER SIDE,
THERE ARE DIFFERENT GENOTYPES
AND IT'S AN RNA VIRUS AND IT'S
VERY LIMITED.
IT'S NOTHING LIKE HEPATITIS C.
>> SAME FOR HEPATITIS C AS AN
RNA VIRUS ONE WOULD EXPECT
DIFFERENT MUTATIONS ARE PRODUCED
DURING REPLICATION AND THERE ARE
SPECIES BUT THERE'S ESSENTIALLY
FOUR MAJOR GENOTYPES, 1 THROUGH
4.
I'M NOT AWARE OF ANY NEW
EMERGING GENOTYPES THAT HAVE
BEEN IDENTIFIED.
OR DIFFERENT DISEASES CAUSED BY
SUB VARIANTS.
>> IS THERE A MODE OF ENTRY INTO
THOSE CELLS SIMILAR TO THE
TRANSPORTER?
IS THAT KNOWN?
>> YOU'RE ASKING ABOUT HEPATITIS
B ENTERING GROUND SQUIRRELS OR
HERONS?
IT'S THE BILE SALT TO ACID
TRANSPORTER AND YOU'RE THE BILE
EXPERT, DR. ARIAS IS, FOR THOSE
WHO DON'T KNOW AMONGST OTHER
THINGS AND THEY FOUND FANTASTIC
STUDIES FROM THE SAN DIEGO ZOO
LOOKING AT BILE IN MULTIPLE
SPECIES SO, YES.
>> AND FOR HEPATITIS E IS THAT
SIMILAR?
>> WE DON'T YET WHAT THE
RECEPTOR IS FOR HEPATITIS E.
THAT'S YET TO BE IDENTIFIED.
ONE THING I'D MENTION TO
COMPLEMENT THEO'S ANSWER IS THE
TRANSPORTING POLY PEPTIDE IS
RESPONSIBLE FOR THE TROPISM OF
HEPATITIS B THAT'S WHY IT'S ONLY
SIGN APES AND HUMANS.
>> WE HAVE A QUESTION WHETHER --
>> NOT THE HUMAN VIRUS.
>> YES, SORRY.
>> ARE EITHER OF THESE VIRUSES
SECRETED IN HUMAN MILK?
>> I'M NOT AWARE OF HEPATITIS E
BEING SECRETED IN HUMAN MILK.
THERE WAS A PAPER PUBLISHED LAST
YEAR SAYING IT'S SECRETED IN
URINE AND URINE MAY BE
CONCENTRATED THERE SO DETECTION
RATES MAY BE HIGHER IN URINE
THAN IN STOOL OR SERUM BUT I'M
NOT AWARE OF STUDIES LOOKING AT
WHETHER IT'S TRANSMITTED IN MOO
-- MATERNAL MILK.
>> IT'S NOT THOUGHT TO BE
SIGNIFICANT AND INFANTS ARE
SCREENED AND VACCINATED IN THE
WEST.
>> THIS IS THE LAST QUESTION AND
WHAT THE QUESTIONER IS ASKING IS
BOTH HEPATITIS D AND E WERE
BASICALLY DISCOVERED BECAUSE OF
PATIENTS WHO WERE SICK WITH
HEPATITIS AND IN THE CASE OF E,
DID NOT HAVE ANY OF THE KNOWN
VIRUSES AT THE TIME SO THE
QUESTIONER IS ASKING WHETHER IT
IS LIKELY THAT THERE ARE OTHER
HEPATITIS VIRUSES OUT THERE AND
ARE THERE WAYS OF ANTICIPATING
THE PRESENCE AND IF THEY'RE
CAPABLE OF CAUSING DISEASE.
ARE THERE EFFORTS TO ANTICIPATE
THE POSSIBILITY OF ADDITIONAL
INFECTIOUS HEPATITIS VIRUSS?
-- VIRUSES?
>> WE THOUGHT FOR A LONG TIME WE
WERE DONE AND THEN COVID CAME
ALONG AND TAUGHT US THERE ARE
OTHER VIRUSES IN OTHER PLACES.
SO HIV IS A SIMILAR STORY.
SO, I THINK WITH THE WAY THINGS
ARE RIGHT NOW AS WE SAID
PREVIOUSLY THERE'S NO OTHER
PREVIOUS FECAL OR TRANSFUSION
TRANSMITTED VIRUS BUT THE
EXHILARATING THING ABOUT
MEDICINE IS THERE'S ALWAYS
SOMETHING NEW TO BE LEARNED.
>> WELL, WE HAVE NO FURTHER
QUESTIONS SO I WANT TO ON BEHALF
OF EVERYONE HERE AND THE AT THE
NIH WHO ARE WATCHING ONLINE AND
AROUND THE WORLD WANT TO THANK
YOU BOTH FOR BRINGING TO OUR
ATTENTION THESE EXTRAORDINARY
DEVELOPMENTS WHICH I DON'T THINK
WERE WIDELY KNOWN AMONGST THE
GENERAL MEDICAL PUBLIC AND
PERHAPS AMONGST OUR STUDENTS SO
THANK YOU VERY MUCH FOR VERY
EXQUISITE 1863 01:41:57,110 PRESENTATIONS