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TODAY WE ARE HONORED TO HAVE DRM
KOTTILIL.
DR. HELLER EARNED HIS
MEDICAL DEGREE AT THE UNIVERSITY
OF WITTER -- SOUTH AFRICA, AND
COMPLETED HIS RESIDENCY TRAINING
IN INTERNAL MEDICINE AT
GEORGETOWN UNIVERSITY.
FOLLOWED BY A POSTDOCTORAL
FELLOWSHIP AT THE NATIONAL
INSTITUTE OF ALLERGY AND
INFECTIOUS DISEASES.
DR. HELLER THEN COMPLETED
FELLOWSHIP TRAINING IN
GASTROENTEROLOGY AND HEPATOLOGY
FELLOWSHIP AT NIDDK, AFTER WHICH
HE JOINED AS STAFF.
DR. HELLER'S SCIENTIFIC
INTERESTS ENCOMPASS CLINICAL
AND -- WORK INCLUDING HEPATITIS
D, RARE LIVER DISEASES AND THE
GUT LIVER AXIS.
HE HAS AUTHORED OR CO-AUTHORED
OVER 250 PAPERS AND BOOK
CHAPTERS.
IN ADDITION TO CONTRIBUTING
CLINICAL MANAGEMENT GUIDELINES
FOR THE MANAGEMENT OF CHRONIC
HEPATITIS C, DEMANDS OF
HEALTHCARE WORKERS LIVING WITH
VIRAL HEPATITIS, AND
ESTABLISHING CRITERIA FOR
CLINICAL TRIALS IN CHRONIC GRAFT
VERSUS HOST DISEASE.
DR. HELLER HAS SERVED AS
EDITORIAL BOARD MEMBER FOR THE
JOURNALS GASTROENTEROLOGY AND
HEPATOLOGY.
HE'S RECEIVED NUMEROUS AWARDS
FOR HIS WORK AS EDUCATOR AND
MENTOR FROM GEORGETOWN
UNIVERSITY HOSPITAL, THE FACULTY
TEACHER AWARD FROM THE DIVISION
OF MEDICINE, DIVISION OF
GASTROENTEROLOGY AND HEPATOLOGY
AT MARYLAND AND IS TWICE
RECIPIENT OF NIDDK'S MENTORSHIP
AWARD AS WELL AS YOU MAKE A
DIFFERENCE AWARD.
HIS CLINICAL RESEARCH HAS BEEN
RECOGNIZED WITH AN NIDDK EARLY
CAREER INVESTIGATOR AWARD, NIAID
MERIT AWARD AND NIDDK INNOVATION
AWARD.
NATIONAL CANCER INSTITUTE
DIRECTOR'S AWARD FOR CLINICAL
SCIENCE.
AND THIS PAST APRIL, DR. HELLER
WAS HONORED TO PRESENT A
CLINICAL CENTER GRAND ROUNDS
DISTINGUISHED CLINICAL RESEARCH
SCHOLAR AND EDUCATOR LECTURE.
DR. KOTTILIL IS INTERIM DIRECTOR
OF THE INSTITUTE OF HUMAN
VIROLOGY AT THE UNIVERSITY OF
MARYLAND SCHOOL OF MEDICINE
WHERE HE'S PROFESSOR OF
MEDICINE, CHIEF OF THE DIVISION
OF INFECTIOUS DISEASES AND
SCIENTIFIC DIRECTOR OF THE NIH
DISTRICT OF COLUMBIA PARTNERSHIP
FOR AIDS PROGRESS.
DR. KOTTILIL EARNED HIS
MEDICAL DEGREE AT GOVERNMENT
MEDICAL COLLEGE IN INDIA, AND
HIS PH.D. FROM CANADA.
HE COMPLETED HIS RESIDENCY IN
INTERNAL RES DEN SEAL AT BROWN
UNIVERSITY AND WAS STAFF
CLINICIAN AT NIAID FROM 2003 TO
2014.
WHERE HE WAS RECIPIENT OF
NUMEROUS BENCH TO BEDSIDE AWARDS
AND OTHERS.
DR. KOTTILIL'S RESEARCH
INTERESTS INCLUDE THE
PATHOGENESIS OF CHRONIC VIRAL
INFECTIONS AND RESEARCH TO
ERADICATE CHRONIC PERSISTENT
VIRAL INFECTIONS BY TARGETING
THE VIRUS AND THE HOST.
HE HAS CONDUCTED SEVERAL
INVESTIGATOR INITIATED STUDIES
IN HEPATITIS C AND HAS SERVED AS
ONE OF THE FOUNDING MEMBERS OF
NATIONAL HEPATITIS C TREATMENT
GUIDANCE PANEL.
A PROLIFIC INVESTIGATOR AND
NATIONALLY RECOGNIZED SPEAKER,
DR. KOTTILIL HAS OVER 300
PEER-REVIEWED PUBLICATIONS AND
BOOK CHAPTERS AND CONTINUES TO
DO WORK SUPPORTED BY NUMEROUS
NIH GRANTS.
HE'S RECIPIENT OF THE HIDNA AND
RICHARD ROSENTHAL AWARD FROM THE
AMERICAN COLLEGE OF PHYSICIANS.
HE HAS AN ELECTED MEMBER OF THE
INFECTIOUS DISEASES SOCIETY OF
AMERICA, AND AMERICAN SOCIETY OF
LIVER DISEASES, AND THE AMERICAN
COLLEGE OF PHYSICIANS.
HE HAS BEEN AWARDED DESIGNATION
OF MASTER BY THE AMERICAN
COLLEGE OF PHYSICIANS.
THE TITLE OF THEIR PRESENTATION
TODAY IS HEPATITIS D AND
POTENTIAL TARGETS FOR TREATMENT.
SO NOW PLEASE JOIN ME IN
WELCOMING OUR SPEAKERS,
DR. HELLER AND DR. KOTTILIL.
[APPLAUSE]
>> THANK YOU FOR THAT VERY KIND
INVITATION.
THANK YOU ALL FOR BEING HERE.
IT'S ESPECIALLY EXCITING FOR ME
TO PRESENT WITH DR. KOTTILIL.
WE'RE OLD FRIENDS, AND HE NEVER
CEASES TO, AS YOU'LL SEE,
IMPRESS WITH HIS INNATE
UNDERSTANDING OF THINGS, HIS
REALLY RAPID ABILITY TO ASSESS
THE SIGNAL FROM THE NOISE, AND I
THINK WHEN HE LEFT THE NIH, IT
WAS A REAL LOSS FOR US.
SO WELCOME BACK.
SO MY PART OF THE TALK IS
PERHAPS IN SOME WAYS SIMPLER,
IT'S JUST TO TELL YOU HOW BAD IT
IS.
JUST TO EXPLAIN HOW DIABOLICAL
THIS VIRUS REALLY IS.
AND I'M GRATEFUL FOR THE
INVITATION TO SPEAK TODAY.
MY DISCLOSURE SLIDE, I WANT TO
ELIMINATE HEPATITIS D.
I'M OBSESSED WITH LIVER DISEASE
AND COFFEE IS ANOTHER OBSESSION
THAT WE -- WE CALL THAT A GOOD
START TO THE DAY, BUT COFFEE --
I DON'T HAVE ANYTHING FINANCIAL
TO DECLARE.
FROM MY PART OF THE TALK, WE'RE
GOING TO UNDERSTAND THE
DIFFICULTY IN IDENTIFYING
PATIENTS INFECTED WITH HEPATITIS
D, AND WE'RE GOING TO UNDERSTAND
HOW TO APPROACH PATIENTS
INFECTED WITH HEPATITIS D.
SO PERHAPS WE COULD START WITH
WHAT IS HEPATITIS D.
IT'S A FANTASTIC STORY.
THTHE DISCOVERY RELATES TO A LOT
OF SEX, INTRIGUE, SERENDIPITY,
UNEXPECTED FINDINGS AND REALLY
DR. ROSETTA'S BRILLIANCE WAS IN
NOT LETTING GO AND SORT OF
PURSUING IT VERY DOGGEDLY AND
UNDERSTANDING THAT THERE WAS
SOMETHING DIFFERENT.
AND THIS IS THE FIRST
DESCRIPTION IN GUT, 1977, 48
YEARS AGO, AND
IMMUNOFLUORESCENCE DETECTION OF
NEW ANTIGEN ANTIBODY SYSTEM,
DELTA FOR DIFFERENT.
THERE WAS NO HEPATITIS C AT THE
TIME SO IT WASN'T THE NEXT
LETTER IN THE ALPHABET.
IT WAS DELTA FOR DIFFERENT.
ASSOCIATED TO HEPATITIS B VIRUS
IN LIVER AND IN SERUM OF
HEPATITIS B ANTIGEN CARRIERS.
WHAT HAPPENED IS THERE WAS A LOT
OF RECONSTRUCTION IN NAPLES AT
THAT TIME, AND IN THE 60s, AND
A LOT OF WOMEN FELT THAT -- FROM
EASTERN EUROPE FELT THAT THOSE
MEN IN NAPLES, THOSE
CONSTRUCTION WORKERS MIGHT BE
LONELY SO THEY WENT TO KEEP THEM
COMPANY, AND AT THE SAME TIME,
THERE WAS THIS MASSIVE OUTBREAK
OF MORE SEVERE HEPATITIS.
HEPATITIS B WAS ALREADY ENDEMIC,
AND THIS OCCURRED ON TOP OF
THAT.
AND WHEN DR. RIZZETTO -- HE WAS
DOING STAINING OF HEPATITIS B IN
THE LIVER AND WHEN HE RAN OUT OF
PATIENT SERA WHICH HE USED TO
STAIN THE LIVERS, HE GOT A FRESH
BATCH AND IT HAPPENED TO BE FROM
A PATIENT THAT JUST HAD DELTA.
AND THEN HE NOTICED THAT SOME OF
THE PATIENTS HAD DIFFERENT
STAINING IN THEIR LIVERS, WHICH
WAS THE DELTA.
HE INITIALLY WASN'T SURE IF IT
WAS AUTOIMMUNE HEPATITIS OR NOT
AND HE CAME TO A YOUNG
RESEARCHER HERE, DR. JAY
HOFFNAGEL, HE MENTIONED HE HAD
THIS AND DR. HOFFNAGEL SAID IN
BUILDING 7 THEY HAVE CHIMPS, WHY
DON'T YOU PUT IT INTO THE CLIM
PS?
CHIMPS?
AGAIN, NIH PLAYED A PIVOTAL
ROLE.
SO YOU'RE GOING TO HEAR THIS
AGAIN, BUT THIS SAID ENOUGH.
WHENEVER WE TALK ABOUT HEPATITIS
D, WE HAVE TO STATE THE
VACCINATION FOR HEPATITIS B IS
THE ULTIMATE CURE FOR HEPATITIS
D.
BECAUSE HEPATITIS D CANNOT EXIST
WITHOUT HEPATITIS B, AND IF YOU
ELIMINATE B, YOU WOULD ELIMINATE
D.
THERE IS NO VACCINE FOR
HEPATITIS D.
WE SHOULD START PERHAPS WITH THE
BAD NEWS.
WHAT IS IT ABOUT HEPATITIS D
THAT'S SO DIFFERENT?
WELL, THERE'S A MUCH FASTER
PROGRESSION TO CIRRHOSIS THAN IN
HEPATITIS B OR HEPATITIS C AND
HEPATITIS C IS ROUGHLY 20% AT 20
YEARS, HEPATITIS B, 30% LIFETIME
RISK.
FOR DELTA, IT'S 10 TO 15% WITHIN
TWO YEARS, 70 TO 90% OVER 10
YEARS.
I ACTUALLY THINK THAT MAY BE A
LITTLE BIT OF AN OVERESTIMATE,
BUT STILL, IT'S DRAMATIC.
THE INCREASED RISK OF LIVER
CANCER OR CARCINOMA COMPARED TO
HEPATITIS B ALONE IS THREE TO
FIVE FOLD AND THE MORTALITY IS
INCREASED MORE THAN TWOFOLD.
SO IT'S DEFINITELY DIFFERENT.
SO WHY DO WE TREAT, WHY ARE
LOOKING FOR THERAPIES, WHY DOES
IT MATTER?
WELL, I'M NOT GOING TO TALK
ABOUT THERAPIES OTHER THAN TO
SHOW YOU THIS.
AT THE CLINICAL CENTER, 13
PATIENTS WERE GIVEN
PEGINTERFERON FOR FIVE YEARS.
30 CONVERTED TO ANTIHBs WITHIN
FIVE YEARS, AND AFTER NINE YEARS
OF FOLLOW-UP, 6 OF THE
7 RESPONDERS WERE ALIVE AND 1 OF
5 OF THE NON-RESPONDERS WERE
ALIVE, SO TREATMENT MAKES A
DIFFERENCE.
AND PERHAPS MOST EXCITINGLY WAS
SOMETHING PUBLISHED IN 1999.
A SINGLE PATIENT WITH DELTA WAS
TREATED WITH INTERFERON FOR 12
YEARS.
CLEAR DELTA BUT MOST
IMPORTANTLY, WENT FROM CIRRHOSIS
TO NORMAL.
AND HERE'S THE HISTOLOGY.
YOU CAN SEE IN PANEL A, PANEL A,
YOU SEE THE SMALL NODULES OF
LIVER TISSUE SURROUNDED BY BLUE
GUFIBROTIC TISSUE.
IN D, IT DOESN'T SAY CIRRHOSIS
IS GONE, IT SAYS NO FIBROSIS WAS
DETECTED.
AND THAT'S OUR AIM.
WE WANT TO GO FROM PANEL A TO
PANEL D.
SO THE WHY.
WE WANT TO DECREASE DEATH, WHICH
IS CAUSED BY HCC OR CIRRHOSIS,
AND WE WANT TO INCREASE
HEPATITIS B SURFACE ANTIGEN ZERO
CONVERSION, WE WANT THE PATIENTS
TO LOSE HEPATITIS B SO THAT THEY
CAN'T GET D AND THE D CAN'T
PROPAGATE, AND IDEALLY WE'D LIKE
THEM TO LOSE HEPATITIS D RNA.
THAT'S AN ASCENDING LIST OF
SURROGATES.
IF YOU GET RID OF THE RNA, GET
RID OF THE HEPATITIS B, GET RID
OF THE CIRRHOSIS, GET RID OF THE
CANCER, GET RID OF THE DEATH.
JUST TO SHOW YOU HOW MUCH HEAP
HEPATITIS D PUNCHES ABOVE ITS
WEIGHT, IN THE EUROPEAN
TRANSPLANT REGISTRY, 25% OF
TRANSPLANTED PATIENTS WITH
HEPATITIS B HAVE HEPATITIS D.
SO IT PUNCHES WAY ABOVE ITS
WEIGHT.
LET'S TALK ABOUT EPIDEMIOLOGY
BECAUSE THAT REALLY MATTERS AS
YOU'LL SEE.
EPIDEMIOLOGY IS VERY CLOUDED BY
WHETHER STUDIES USE ANTIBODY OR
VIRUS, WHETHER THEY ASSESSED THE
PRESENCE OF HEPATITIS D IN
TERTIARY CARE CENTERS, IN HOT
SPOTS, IN PRIMARY CARE SETTINGS,
IN BLOOD DONORS. IN EACH
SETTING THERE'S DIFFERENT
PROBABILITY OF FINDING HEPATITIS
D.
TREMENDOUS ASSAY VARIABILITY.
AND I'M GOING TO COME BACK TO
THAT.
AND THE MOST IMPORTANT THING,
JUST THE IGNORANCE AND LACK OF
TESTING.
"HOWEVER, DESPITE 40 YEARS, IT
WAS 40 YEARS AT THE TIME, OF
EPIDEMIOLOGICAL SURVEYS, THE
GLOBAL NUMBER OF INFECTED
PATIENTS REMAINS UNDEFINED.
48 TO 60 MILLION, 62 TO
72 MILLION, 12 MILLION.
THAT'S VERY DIFFERENT.
THESE WIDELY DIFFERENT FIGURES
EMPHASIZE THE HETEROGENEITY OF
REPORTS ON HEPATITIS D, AND A
LACK OF SUFFICIENT QUALITY DATA.
THE EMPHASIS IS MINE.
THUS, INADEQUATE SCREENING,
TECHNICAL LIMITATIONS AND LACK
OF TESTING ARE PROBLEMS.
IF WE LOOK AT THE GLOBAL MAP,
WHAT YOU CAN SEE IS HOT SPOTS.
THE FIRST THING THAT JUMPS OUT
IS AREAS WHERE THERE'S A LOT OF
HEPATITIS D.
THESE AREAS, MONGOLIA, THE DELTA
BELT AND PAKISTAN, PARTS OF AFER
AFRICA, THE AMAZON BASIN, WHERE
THERE'S A VERY HIGH PREVALENCE
OF HEPATITIS D.
IT'S NOT UNDERSTOOD WHY.
PARTIALLY BUT NOT COMPLETED OF .
YOU CAN SEE THERE'S QUITE A
RANGE OF PREVALENCE, AND LASTLY,
THERE'S DIFFERENT GENOTYPES.
AND THIS IS IMPORTANT FOR A
NUMBER OF REASONS.
THE GENOTYPE ONE IS FOUND
GLOBALLY, 2 AND 4 IN ASIA, # IN
SOUTH MAYOR KA, BUT 5, 6, 7 AND
8 ARE FOUND IN AFRICA.
THE PROBLEM WITH 5, 6, 7 AND
8 ARE THEY MOST DIVERGENT, THE
LAST TO BE FOUND A LOT OF THE
OLDER ASSAYS DON'T DETECT THEM.
SO IN PATIENTS FROM AFRICA, WHEN
THEY COME TO THE WEST OFTEN THE
DELTA IS MISSED AND IN A LOT OF
EPIDEMIOLOGIC SURVEY, DELTA IS
MISSED.
WHAT ABOUT AMERICA?
IN NORTHERN CALIFORNIA, 1191
PATIENTS TESTED, AND 499 FOR
HEPATITIS B.
OF THEM, ALMOST 500 WERE TESTED
FOR HEPATITIS B, 42 PEST, THAT
42%, MUCHHIGHER THAN THE TYPICAE
IF YOU LOOK IN STUDIES LIKE
THIS, BUT I'M USING THIS TO SHOW
YOU THAT 8% OF THE PATIENTS
TESTED WERE POSITIVE.
IN A VETERAN POPULATION DONE BY
TATIANA KUSHNER, WHO WAS A
FELLOW AT THE TIME, AND FOR THE
FELLOWS LISTENING, OR MAYBE NOT
LILISTENING, TATIANA WAS A FELLW
AT U-PENN, AND I GAVE A TALK,
AND I WAS TALKING -- SAID HOW
IMPORTANT I THINK DELTA IS AND
SHE SAID, BUT THAT'S VERY NICE
BUT WE JUST DON'T SEE ANY IN
AMERICA.
AND I SAID THAT'S BECAUSE YOU
DON'T TEST.
AND WE GOT INTO THIS WHOLE
DISCUSSION.
AND AS A FELLOW, SHE THEN WENT
TO THE U.S. VETERAN POPULATION
DATABASE AND SHE SHOWED THAT 25
THOWL 600 PATIENTS WERE FOUND TO
HAVE HEPATITIS B.
ONLY 8 1/2% WERE TESTED, A
LITTLE BIT OVER 2,000, AND 73,
THAT'S 3.4%, WERE POSITIVE FOR
HEPATITIS D.
AND IF WE THINK THAT THESE ARE
THE PATIENTS THAT ARE GOING TO
GET TRANSPLANTED AND THESE ARE
THE PATIENTS WHO ARE GOING TO
DIE, THAT'S A LOT.
3.4%.
AND ONLY 8 1/2% TESTED IS NOT
ENOUGH.
AND IT WAS PUBLISHED IN J
HEPATOLOGY, NICE FELLOW PROJECT.
WHAT ABOUT THE EPIDEMIOLOGY?
A PAPER FROM HERE LOOKING AT 588
PATIENTS, SHOWED INACTIVE
HEPATITIS B WITH A LEVEL LESS
THAN 2,000.
WE'RE GOING TO COME BACK TO
THAT.
AN ELEVATED ALT WITH A LOW LEVEL
HEPATITIS B SHOULD MAKE YOU
THINK ABOUT DELTA.
AND THEN THE CLASSIC RISK
FACTORS IN NORTH AMERICA,
INTRAVENOUS DRUG USE, AND
HEPATITIS D ENDEMIC COUNTRY OF
ORIGIN.
REMEMBER THOSE HOT SPOTS THAT I
SHOWED YOU, THOSE RED AREAS ON
THE MAP?
IF PEOPLE COME FROM THOSE AREA,
VERY LIKELY TO HAVE HEPATITIS D
WITH HEPATITIS B.
AND IF WE LOOK AT THE
GUIDELINES, EASEL SAYS TEST
EVERYONE, THAT'S THE EUROPEAN
ASSOCIATION FOR THE STUDY OF
LIVER DISEASE, EVERYONE HAS
HEPATITIS B.
SHOULD BE CHECKED FOR D, C, AND
HIV.
APASL OR THE ASIAN GUIDELINES
SAID THE SAME.
BUT THE AMERICAN GUIDELINES SAY
INACTIVE HEPATITIS B OR PEOPLE
AT RISK.
THE PROBLEM IS WE DON'T FOLLOW
THOSE GUIDELINES, AND I WANT TO
USE ONE PATIENT TO ILLUSTRATE
THAT.
49-YEAR-OLD MALE BORN IN IDAHO,
JOHN PUBLIC, MARRIED WITH TWO
CHILDREN, OUTSTANDING CITIZEN,
INVOLVED IN HIS COMMUNITY.
HE HAD HIS COLONOSCOPY AND HIS
ASTUTE GASTROENTEROLOGIST
NOTICED HE WAS CIRRHOTIC AND
NOTICE THAT HIS HEPATITIS B WAS
ACTIVE, 150,000, AND E ANTIGEN
POSITIVE.
AND HE TREATED HIM, BUT THEN HE
WENT ON TO DEVELOP
CHOLANGIOCARCINOMA.
HE HAD MULTIPLE, MULTIPLE
ENCOUNTERS WITH THE MEDICAL
SYSTEM, BUT IT TOOK AN ASTUTE
ONCOLOGIST TO CHECK HIM AND FIND
THAT HE'S HEPATITIS D POSITIVE.
NO ONE KNEW ABOUT HIS YOUTHFUL
INDISCRETIONS, NOT EVEN HIS
WIFE.
SO IT DOESN'T MATTER IF YOU ASK
OR DON'T ASK.
THI THINK THE IMPORTANT THING IS
TO TEST.
I KNOW HIS STORY IS ANECDOTAL,
BUT THERE'S A NICE PAPER IN J
H EP IN 2014 SHOWING BOTH ARE
DOMINANT, OFTEN IT'S NOT JUST
HEPATITIS B WHICH IS DOMINANT,
SORRY, HEPATITIS D THAT'S
DOMINANT, WHICH IS THE BLUE IN
THAT PIE CHART.
AND IF YOU LOOK AT A SECOND
PAPER, WHICH IS A LITTLE BIT
MORE COMPLEX, ESSENTIALLY THE
SAME THING.
THE HEPATITIS D DOMINANCE IS THE
BLUE AND THE ORANGE.
SO 44% AND 39% OF PATIENTS IN
TWO SERIES, TWO LARGE SERIES, DO
NOT HAVE HEPATITIS B AS
DOMINANCE, SO IT SHOULDN'T SHOP
YOU FROM TESTING.
WHY THE EMPHASIS?
AND IF YOU ALLOW ME TO INVOKE A
PREVIOUS NIH DIRECTOR FROM A
DIFFERENT ERA, IN HIS -- IN
DR. VARMUS' BOOK ABOUT THE ART
AND POLITICS OF SCIENCE, HE
POINTS OUT THAT MANY NOBEL
PRIZES HAVE BEEN GIVEN FOR THE
ABILITY TO MEASURE SOMETHING OR
SEE SOMETHING.
IF YOU CAN'T MEASURE IT, YOU
CAN'T SEE IT, YOU CAN'T STUDY
IT.
YOU HAVE TO BE ABLE TO DETECT IT
AND YOU HAVE TO BE ABLE TO
DETECT IT ACCURATELY.
SO TEST EVERYONE WITH HEPATITIS
B.
AND I WOULD SUGGEST USING AN
ANTIBODY AS A SCREEN AND IN
HEPATITIS D, PCR TO CONFIRM.
THERE ARE NOW COMMERCIALLY
AVAILABLE ASSAYS.
AND IT'S KEY TO CONFIRM WITH THE
PCR, BECAUSE SOME PATIENTS WILL
CLEAR.
OKAY, WHAT NEXT?
LET'S GO BACK TO BASICS.
TRANSMITTED THROUGH BLOOD AND
BODY FLUIDS.
IT'S ACQUIRED IN TWO WAYS,
EITHER COINFECTION, THAT MEANS
YOU GET B AND D TOGETHER, YOU
HAVE SEX OR SHARE NEEDLES WITH
SOMEONE WHO HAS BOTH VIRUSES AND
YOU GET INFECTED WITH BOTH
VIRUSES.
THAT'S OFTEN ACUTE AND OFTEN
VERY SEVERE.
AND THE RISK OF CROW NIS IT IS S
VERY LOW.
IT DEPENDS ON THE AGE OF THE
PERSON BUT IN AN ADULT, IT'S
ABOUT 2%.
THE SECOND IS SUPER INFECTION.
THIS IS OFTEN MISSED, AND 90% OF
THESE PATIENTS BECOME CHRONIC.
REMEMBER THE STORY ABOUT NAPLES,
HEPATITIS SUPERIMPOSED ON TOP OF
THAT?
MOST OF THEM BECAME CHRONIC.
THIS IS WHAT IT LOOKS LIKE.
IN THE TOP CURVE, THE HEPATITIS
B DNA IS THE YELLOW.
THE D RNA IS THAT LITTLE BLUE
BLIP HIDING BETWEEN THE GREY AND
THE YELLOW.
AND THE LT IS THE DOTTED LINE.
AND IF YOU GO TO THE BOTTOM
CURVE, WHICH IS SUPER INFECTION,
THE GREY IS THE HEPATITIS B
SURFACE ANTIGEN.
THE ALT, THAT DOTTED RED LINE
MAKES A LITTLE JUMP UP AND THEN
RE-ADJUST TO A NEW NORMAL HIGHER
BASELINE AND THE HEPATITIS D RNA
TAKES OVER AND BECOMES DOMINANT.
SO IT REALLY INTERESTING BEFORE
WE TALK ABOUT THE VIROLOGY, I
SHOULD POINT OUT THE CLOSEST
RELATIVE TO HEPATITIS D IS THE
PLANT VIROID.
THERE'S NO OTHER VIROID, I USE
THAT WORD BECAUSE IT'S
INCOMPLETE, IT'S NOT REALLY A
VIRUS, IT'S ABSOLUTELY DEPENDENT
ON HEPATITIS B BUT IT STILL
ESTABLISHES DOMINANCE IN MORE
THAN HALF OF PATIENTS.
SO INTERESTING AND SNEAKY.
IT'S A SINGLE NEGATIVE SENSE
RNA.
1700 NUCLEOTIDES, SO TINY.
THE SMALLEST PATHOGENIC VIRUS IN
HUMANS.
THERE ARE OTHER VIRUS, BUT IT'S
THE SMALLEST PATHOGENIC VIRUS.
IT'S COVALENTLY CLOSED AND TAKES
THIS ROD SHAPED STRUCTURE AND IT
WAS PUBLISHED IN SCIENCE IN THE
60s AND IT FORMS MULTIPLE BASE
PAIRS, ALMOST LIKE DNA AND WE'RE
GOING TO COME BACK TO THAT, AND
IT'S SURROUNDED BY HEPATITIS D
LARGE AND SMALL ANTIGEN, IF YOU
LOOK AT THE TOP FIGURE.
AND THEN IT'S ENCASED IN THE
HEPATITIS B ENVELOPE.
HEPATITIS B IS BELOW THAT.
COMPLERK STRUCTURE.
TREMENDOUS PROGRESS HAS BEEN
MADE.
WE NOW UNDERSTAND A LARGE PART
OF THE VIRUS LIFECYCLE.
IT REALLY A TRIUMPH OF MOLECULAR
VIROLOGY AND MOSTLY NIH FUNDING.
TIT'S AN EXAMPLE OF DELAYED
GRATIFICATION BECAUSE IT'S THE
PURSUIT OF SCIENCE WITHOUT
IMMEDIATE OBVIOUS APPLICATION.
WHEN PEOPLE WERE STUDYING AND
LOOKING AT THIS, THEY DIDN'T
UNDERSTAND THEIR INSIGHTS AT THE
TIME WOULD LEAD TO DRUG
DISCOVERY.
AND JUST ONE SMALL THING.
HOST DNA DEPENDENT RNA
POLYMERASES -- TRANSCRIPTION OF
HEPATITIS D ANTIGEN MRNA.
YOU CAN'T DO THAT IN A TEST TUBE
IF YOU TRIED.
RNA DEPENDENT -- RNA POLYMERASES
MAKE RNA FROM RNA TEMPLATE, BUT
HERE YOU'RE TAKING A DNA
DEPENDENT RNA PLER ACE AND USING
TO MAKE RNA FROM RNA.
IT'S PRETTY INTERESTING.
SO LIKE ANY SELF RESPECTING
VIRUS THAT HAS TO GET INTO THE
CELL, A VIROID, IT'S ENCASED IN
HEPATITIS B AND IT GETS IN
THROUGH THE TRANSPORT PROTEIN,
AND ONCE IN THE CELL, REPLICATES
IN THE NUCLEUS, IT'S NEGATIVE
SENSE SO POSITIVE SENSE GETS
TRANSCRIBED.
IT THEN REPLICATES INSIDE THE
NUCLEUS SO WE'RE GOING TO COME
BACK TO THAT IN THE NEXT SLIDE,
WE'RE GOING TO TALK ABOUT THAT
IN A LITTLE BIT MORE DETAIL.
IT'S SENT OUT TO THE CYTOPLASM
WHERE IT'S TRANSLATED INTO
PROTEIN, AND THEN SETTLE BACK
INTO THE NUCLEUS TO FORM THE
RIBONUCLEAR PROTEIN WHICH THEN
GETS SHUTTLED INTO THE NUCLEUS
INTO THE ENDOPLASMIC RETICULUM
TO BE ENCAPSULATED INTO THE
HEPATITIS B ENVELOPE WITH THE
HEPATITIS B SURFACE ANTIGEN, AND
THAT WILL THEN BE SENT OUT OF
THE CELL TO GO INFECT SOME OTHER
CELLS OR SOME OTHER PERSON.
SO I WANT TO FOCUS JUST A LITTLE
BIT ON ONE ASPECT OF REPLICATION
BECAUSE I THINK IT SAYS SO MUCH
ABOUT HOW INTERESTING THIS VIRUS
IS.
THERE ARE TWO PROTEINS.
IT RELIES COMPLETELY, ALL OF
THAT THAT I JUST SHOWED YOU, ALL
OF THIS RELIES ON HOST PROTEINS.
FOR REPLICATION.
THE VIRUS ITSELF DOES VIROID,
ENCODE ANY OF ITS OWN PROTEINS.
IT HAS AN ENZYME BUT IT CLEAVES
ITSELF.
IT HAS A RIBOZYME, THAT'S A PART
OF THE RNA THAT CLEAVES THE RNA
FROM CLOSED TO OPEN ON A LINEAR
STRAND OF RNA.
EVERYTHING ELSE IS COMPLETELY
DEPENDENT DENT ON THE HOST
MACHINERY WHICH EXPLAINS WHY
IT'S BEEN SO DIFFICULT TO COME
UP WITH THERAPIES FOR IT.
THE INITIAL PLUS STRAND HAS AN A
IN CODON 196, WHICH FORMS AN
AMBER STOP CODON, UAG.
AND IT MAKES THIS PROTEIN WITH
THWHERE THAT STOP CODON IS THE
SMALL DELTA ANTIGEN AND THAT WAS
REQUIRED FOR REPLICATION.
THERE'S A HOST DEFENSE PROTEIN
ENZYME CALLED AD1 AND THIS IS
INDUCED BY INTERFERON.
SO THIS IS INDUCED BY OUR
DEFENSE AGAINST THE VIRUS.
THIS PROTEIN, THIS ENZYME
FORMALLY CAUSES CHAOS MUTATIONS.
IT CAUSES MUTATIONS IN
RETROVIRUSES THAT WILL MAKE THEM
DEFECTIVE UNLESS ABLE TO
REPLICATE.
HEPATITIS D TAKES THIS PROTEIN,
IT LAUGHS AT IT, AND IT USES TO
MUTATE THAT A TO A G.
THAT CODON 196 NOW BECOMES
ATRYPTOPHAN, AND THE PROTEIN
GETS EXTENDED 17 TO 19 AMINO
ACIDS FURTHER, AND THAT
EXTENSION, DEPENDING ON THE
GENOTYPE 17 TO 19, NOW HAS A
SITE THERE, WHICH IS A CXX
MOTIF, WHICH.
THAT'S INCREDIBLY IMPORTANT
BECAUSE THAT MOTIF ALLOWS A
JOURNAL-JOURNAL TRANSFERASE, A
HOST PROTEIN, HOST ENZYME, TO
THEN TAKE A PARENTAL GROUP,
ATTACH TO THE PROTEIN, WHICH
ALLOWS TO INSERT ITSELF INTO THE
HEPATITIS B MEMBRANE.
SO LET'S THINK ABOUT IT.
IT TAKES A HOST PROTEIN WHICH
SHOULD BE DEFENDING US AGAINST
VIRUSES, IT THEN USES THAT TO
GET RID OF A STOP CODON TO MAKE
A LARGE ANTIGEN WHICH NOW
INCLUDES A MOTIF WHICH ALLOWS TO
INSERT INTO HEPATITIS B ENVELOPE
WHICH IT LETS IT GET OUT OF THE
CELL.
IT'S DIABOLICAL.
SO YOUR WE SO NOW WE HAVE AN IND
HUMAN.
WE YOU UNDERSTAND STAND THE
LIFECYCLE, WE UNDERSTAND HOW THE
VIRUS GET OUT AND TRANSMITTED TO
THE NEXT PERSON.
SO BEFORE I HAND OVER TO
DR. KOTTILIL, LET'S SUMMARIZE.
48 YEARS WE'RE STILL STRUGGLING.
STRUGGLE IS REAL.
BUT SLOWLY, SLOWLY.
SO IT'S LIKE THE OLD JOKE, THE
SON COMES HOME FROM SCHOOL, HIS
MOTHER SAYS WHAT DID YOU LEARN
TODAY?
HE SAYS NOT ENOUGH.
SHE SAYS WHY DO YOU SAY THAT?
HE SAYS BECAUSE WE HAVE TO COME
BACK TOMORROW.
SO THE SAME THING HERE, WE HAVE
TO KEEP GOING.
HEPATITIS D IS FASCINATING.
THE EPIDEMIOLOGY IS NOT ALWAYS
PREDICTABLE, BUT IT'S SOMEWHAT
UNDERSTOOD.
WE HAVE LOW RESOLUTION IMAGES.
DIAGNOSTIC ASSAYS ARE STILL
LACKING BUT THE CLINICAL CENTER
IS ABOUT TO BE INVOLVED IN A
STUDY WITH ROCHE TO DEVELOP AN
ASSAY TO LICENSE THEIR ASSAY FOR
NORTH AMERICA, WHICH WILL DETECT
GENOTYPES 1 THROUGH 8.
BIOLOGY IS INCREDIBLE.
THE WHOLE THING, RIBOZYMES,
MOTIFS, THINK ABOUT IT AS A
MODEL FOR CLINICIANS.
HERE YOU HAVE A DISEASE WHERE
RAPIDLY AND REPRODUCIBLY 70 TO
90% WILL DEVELOP FIBROSIS IN 10
YEARS.
IMAGINE IF YOU WANT TO
UNDERSTAND FIBROSIS DEVELOPMENT.
AND FASCINATING THIS THAT IT GP
EVERYTHING AND SHRUNK DOWN TO
ALMOST EXCLUSIVELY IN HOST
REPLICATION.
WHAT YOU'RE ABOUT TO HEAR IN THE
NEXT SECTION OF THE TALK IS A
REVOLUTION IN SCIENCE-BASED
THERAPEUTICS.
I WANT TO THANK THE PATIENTS,
NURSES, FELLOWS, COLLABORATORS,
DR. CHRISTOPHER IS ABOUT TO DO
SOME REEL REALLY INNOVATIVE
THERAPEUTIC STUDIES HERE AT THE
CLINICAL CENTER, THE PATHOLOGIST
WE WORK WITH WHO MAKES
EVERYTHING POSSIBLE,
DR. KLEINER, DR. LIANG, THE MOST
INCREDIBLE LIVER DISEASE BRANCH
WHERE ALL OF THIS WORK HAPPENS,
HE'S CREATING AN ENVIRONMENT
WHERE GROWTH AND INNOVATION IS
POSSIBLE, AND DR. HOOFNAGLE, WHO
DID SOME OF THE VERY FIRST
INTERFERON STUDIES EVER WITH
HEPATITIS D.
AND THAT'S A PICTURE OF THE
GROUP WITH DR. LIANG IN THE
CENTER.
DR. HOOFNAGLE NEXT TO HIM AND
DR. KLEINER ON THE OTHER SIDE.
I JUST WANT TO REMIND YOU, FROM
PANEL A TO PANEL D, THAT'S WHAT
WE'RE AIMING FOR.
WE DON'T WANT CIRRHOSIS, WE WANT
TO ELIMINATE CIRRHOSIS, WE WANT
TO ELIMINATE DEATH, WE WANT TO
ELIMINATE THE VIRUS, AND WE WANT
EVERYONE'S LIVER TO BE THE
NORMAL.
MAYA ANGELOU SAID IT BEST, LIFE
LOVES THE LIVER OF IT.
THANK YOU.
[APPLAUSE]
>> THANK YOU FOR THAT
INTRODUCTION.
IT'S A GREAT HONOR TO GIVE THIS
TALK WITH THEOHELLER, WHO'S
DEDICATED A LOT OF TIME IN
STUDYING HEPATITIS DELTA FOR
MANY YEARS.
MUCH HE KNOWS DELTA INSIDE AND
OUT MORE THAN I DO.
I'LL TRY TO SUMMARIZE SOME OF
THE ASPECTS OF IT THAT LOOK TO
THE NEW PROMISING THERAPEUTICS
THAT HAS COME UP IN HEPATITIS
DELTA.
THESE ARE MY DISCLOSURES.
NOTHING BIG DEAL RELATED TO THE
PRESENTATION.
I WILL BE DISCUSSING MOST OF THE
STUFF WHICH IS NOT FDA-APPROVED.
THE OBJECTIVE IS TO JUST
UNDERSTAND THAT AGNOSTIC
CRITERIA, SOME OF WHICH WAS JUST
COVERED, AND THERAPEUTIC
PIPELINE AND ALSO THE CORRELATES
IN IMMUNE AND CLINICAL END
POINTS THAT GUIDE THERAPEUTIC
RESPONSE FOR HEPATITIS DELTA.
AS DR. HELLER MENTIONED,
HEPATITIS DELTA IS AN ENANYTHING
MA, THERE ARE POCKETS OF
INFECTION REPORTED HIGH IN
PLACES LIKE MONGOLIA, PAKISTAN
AND TURKEY, BUT MANY OF THESE
THINGS ARE VERY SMALL STUDIES
AND THE REAL PREVALENCE OF DELTA
IS NOT REALLY UNDERSTOOD.
MOST OF THE GUIDANCE AND
SCREENING IS STILL BASED ON
WHERE YOU ARE FROM RATHER THAN
FROM CHARACTERISTICS.
THERE WAS A CLASSIC STUDY IN THE
80s IN HIV, YOU DO HIV
SEROLOGY TESTING IN PEOPLE AT
HIGH RISK FOR HIV, YOU HAVE
SCREENING SENSE AT SENSITIVITYF
PEOPLE WHO INJECT DRUGS, 100%
PREDICTIVE VALUE.
YOU TAKE THE SAME TEST AND GO TO
MIDWEST AND TEST KINDERGARTEN
TEACHERS, YOU SEE THE
SENSITIVITY POSITIVITY VALUE
DROPS TO 50%.
SAME IS TRUE HERE.
ANY TEST YOU HAVE, THE
PREVALENCE DETERMINES THE
POSITIVITY VL EU.
IF YOU LOOK AT -- SCREENING, YOU
HAVE TO SCREEN A LOT OF PEOPLE
WHO ARE INFECTED BUT IF YOU LOOK
TO PEOPLE WHO ARE SPECIFICALLY
FOCUSED WITH LIVER DISEASE AS
WAS MENTIONED BY DR. HELLER, YOU
ARE LIKELY TO FIND MORE
HEPATITIS DELTA.
IT WAS MENTIONED BEFORE THAT WHO
GETS DELTA, I WANT TO QUICKLY
GO -- THERE ARE TWO WAYS YOU GET
IT, EITHER COINFECTION, WHERE
YOU GET BOTH B AND C TOGETHER,
OR YOU SOMETIMES CAN GET A
CHRONIC HEPATITIS B ON TOP OF
THAT, YOU GET THE SECOND
EXPOSURE AND YOU GET A CHRONIC
DELTA INFECTION ESTABLISHED.
THIS -- THE FIRST ONE IS
IMPORTANT, THE ONLY ONE REALLY
GOOD STRATEGY THAT WE HAVE TODAY
IS TO PREVENT HEPATITIS B.
SO IF YOU DON'T HAVE HEPATITIS
B, YOU WON'T GET HEPATITIS
DELTA.
EARLIER COINFECTION IS
COMPLETELY -- OF VACCINES AND
MANY OF THESE PLACES THE VACCINE
UP TAKE FOR HEPATITIS B WAS NOT
GREAT UNTIL RECENTLY, SO THAT'S
ONE OF THE REASONS WHY YOU HAVE
COINFECTIONS WITH DELTA AT ALL.
THE SECOND SCENARIO IS IF YOU
HAVE COINFECTION BECAUSE OF
CONTINUED RISK FACTOR THAT
PEOPLE MAY HAVE.
YOU HAVE A PATIENT WHO IS
ACUTELY DISEASE -- SO THE FIRST
ALGORITHM IS THAT YOU HAVE
SOMEONE COME IN, YOU SCREEN FOR
HEPATITIS VIRUSES, AND IF THEY
TURN OUT HEPATITIS B POSITIVE,
THEN YOU LOOK FOR ACUTE OR
HEPATITIS B.
-- TEST FOR HDV WITH RNA.
IF THEY ARE RNA POSITIVE THEY
HAVE DELTA AND RNA NEGATIVE,
THEY DON'T.
BUT IF YOU HAVE -- YOU DO NOT
HAVE A -- FOR HEPATITIS B THEN
YOU HAVE CHRONIC HEPATITIS B.
SO THEN YOU STILL GO TO THE
RIGHT SIDE OF THE ALGORITHM,
WHERE YOU TEST FOR IMMUNOIGM FOR
HEPATITIS DELTA.
IF SEROLOGY IS POSITIVE THEN YOU
LOOK FOR RNA.
SEROLOGY IS POSITIVE AND IF RNA
IS NEGATIVE, THEY HAVE RESOLVED
INFECTION AND IF THE RNA IS
POSITIVE YOU HAVE A CHRONIC
HEPATITIS DELTA.
SO THAT'S THE USUAL ALGORITHM.
WHO SHOULD BE TESTED?
DR. HELLER POINTED OUT THIS IS
VERY DIFFICULT AFTER TIME, IT IS
NOT REALLY UNDERTAKEN.
THETHE GUIDELINES ARE VERY
RESTRICTIVE.
SOME PEOPLE SAY EVERYBODY SHOULD
BE TESTED, BUT WE ACTUALLY DO
NOT DO THAT IN REGULAR PRACTICE.
I JUST WANT TO GO OVER THE
UNIVERSAL TESTING IS VERY
DIFFICULT BECAUSE WE DON'T
REALLY HAVE GOOD ASSAYS AND
THAT'S ONE OF THE BIG PROBLEMS
OF DEVELOPING POSITIVE, FALSE
POSITIVE, FALSE NEGATIVE.
WE DON'T REALLY HAVE AN
FDA-APPROVED PCR FOR DELTA WHICH
IS THE BACK BOAP OF TREATMENT
RESPONSE AND THAT'S WHAT
DR. HELLER MENTIONED THAT ROCHE
IS LOOKING INTO DEVELOPING SUCH
A PLATFORM ASSAY.
I WILL JUST GO THROUGH THE --
MANY TESTING THAT WORKED FOR
HEPATITIS B AND HEPATITIS C
REFLECTS UNIVERSAL TESTING --
DOESN'T REALLY PAN OUT HERE
BECAUSE YOU'D HAVE TO TEST A LOT
OF PEOPLE TO FIND DELTA.
THE LAST LINE IS WHAT I READ
THAT UNIVERSAL SCREENING IS
COST-EFFECTIVE IF YOU HAVE LOW
PREVALENCE OF HEPATITIS B AND
HIGH PREVALENCE OF DELTA.
IT'S NOT GOING TO BE
COST-EFFECTIVE IF YOU HAVE VERY
HIGH PROBLEMS WITH HBV AND
REALLY LOW PROBLEMS OF DELTA
COINFECTION.
WE NEED TO KNOW THAT THE
PREVENTIVE VACCINE IS --
HEPATITIS B IS AVAILABLE, AND
THAT'S UPTAKE OF THE VACCINE
WILL HELP CONTROL CHRONIC
HEPATITIS B AS DELTA.
THE TREATMENT, THERE'S NO
FDA-APPROVED TREATMENT, BUT THE
TREATMENT THAT MOST PEOPLE USE
IS INTERFERON ALPHA.
-- FOR US TO FIND OUT THAT THE
LIVER ISN'T DAMAGED AND YOU
DON'T HAVE CARCINOMA.
HAVING DELTA COINFECTION WILL
INCREASE THE CHANCES OF GETTING
INFECTION, MULTIPLE FOLD AND
DEVELOP CIRRHOSIS, SO THIS IS
WHAT HAPPENS AND THE CONCEPT IS
THAT YOU HAVE AP ANTIVIRAL
TREATMENT THAT CAN SLOW THIS
PROCESS DOWN.
REALLY WE DON'T HAVE
THERAPEUTICS OR FUNCTIONAL CURE
FOR HEPATITIS DELTA YET BUT AT
LEAST THE THERAPEUTICS WILL
OFFER YOU SOME SLOWING OF THE
PROCESS.
DR. HELLER MENTIONED SEVERAL
THERAPEUTICS ARE BEING
DEVELOPED.
THIS IS A REALLY CONCISE WAY OF
LOOKING AT ONE OF THE ENTRY
INHIBITOR.
THERE ARE AGENTS LIKE INTERFERON
TO BLOCK DIFFERENT ASPECTS OF
HDV REPLICATION, AND YOU HAVE
RNA AGENTS -- SO THEY CAN BLOCK
DELTA TRANSCRIPTION AND
INTERRUPT THE LIFECYCLE.
THE GREAT -- WHICH I'LL GET INTO
IT IS AN INHIBITOR THAT HAS BEEN
USED AN ALSO THIS NUCLEIC ACID
POLYMER THAT IS ALSO --
ANTIVIRAL ACTIVITY.
THERE ARE AGENTS THAT MAY WORK
IN BOOSTING IMMUNE RESPONSE,
VERY EARLY CLINICAL STAGES ARE
IN CONCEPT, NOT DEVELOPED YET.
CLINICAL END POINTS FOR --
DELTA.
USUALLY CAN YOU DO FINITE
TREATMENT PARADIGMS OR YOU CAN
ACTUALLY USE MAINTENANCE LONG
TERM TREATMENT RESPONSE.
I SHOW YOU BOTH DATA -- RESPONSE
TIME IS YOU CAN TREAT FOR SOME
TIME AND THEN STOP TREATMENT AND
SEE WHETHER WE ACTUALLY HAVE
LED -- BELOW THE LEVEL OF
DETECTION.
THE CLASSIC EXAMPLE, THEY DID
THE STUDY OF 41 PATIENTS WITH
HEP C, TREATED THEM AT SIX
MONTHS WITH INTERFERON THEN
STOPPED TREATMENT.
SIX MONTHS LATER, WE FOUND THAT
PERCENTAGE OF PEOPLE ACTUALLY
HAD NO DETECTABLE HEPATITIS C
THAT WAS REALLY LANDMARK TO BE
ABLE TO SAY THAT HEPATITIS C CAN
ACHIEVE A FUNCTIONAL CURE.
AND THAT'S THE KEET STEP FOR
THAT.
SO THAT'S A VERY -- SOME STUDIES
HAVE LOOKED AT FINITE TREATMENT.
THE MAJORITY OF NEWER STUDIES
HAVE LOOKED AT MAINTENANCE
TREATMENT, BECAUSE THEY DON'T
THINK THE FUNCTIONAL TREATMENT
IS ACHIEVABLE WITH THE
CURRENT -- AT THIS TIME SO MOST
OF THESE ARE LOOKING AT WHETHER
THERE'S A DECLINE THAT LEADS
TO -- IF THERE'S NORMAL ALT
THERE IS LESS INFLAMMATION.
SO THE COMBINED RESPONSE IS WHAT
I WOULD REFER TO MOST PART AND
IT'S SOMETHING THAT MOST OF THE
DRUG STUDIES HAVE BEEN DONE THAT
HAVE LED TO THIS PART.
INTERFERON IS DEFINITELY USED,
I'M NOT GOING TO SPEND A LOT OF
TIME.
THE REASON IS THAT HEPATITIS
DELTA, EVERYBODY KNEW DELTA --
COINFECTION WILL LEAD TO RAPID
DEVELOPMENT OF FIBROSIS AND WE
HAD TO TREAT THESE PEOPLE AND
THERE WAS NOTHING AVAILABLE SO
MANY OF THESE STUDIES, PATIENT
ARE TREATED WITH INTERFERON
ALPHA.
IT DEFINITELY HAS SOME SUCCESS.
INTERFERON STUDIES WERE DONE AS
FINITE STUDIES, AND THIS HAS
BEEN DONE MANY YEARS AGO.
YOU HAVE REALLY HAD GOOD DATA ON
THE LONG TERM CON QENSES ON WHAT
HAPPENS -- DECOMPENSATION, ET
CETERA, LATER ON WHICH DOESN'T
EXIST FOR THE NEWER TREATMENT.
SO -- EVEN THOUGH IT DOESN'T
REALLY TRANSLATE INTO SUCCESS OF
CURING A LOT OF PEOPLE, IT STILL
HAS BEEN SUCCESSFULLY SHOWN THAT
IT DOES HAVE REALLY GOOD
RESPONSE, GOOD THERAPEUTIC
OPTION FOR PEOPLE WITH CHRONIC
HEPATITIS B.
THE FIRST ONE I GO TO, FIRST
DEVELOPED -- VERY SIMILAR TO
IMMUNO -- VERY SIMILAR -- THAT
WILL CONTINUALLY BLOCK -- AND
BLOCK ENTRY.
IT WAS INITIALLY DEVELOPED FOR
TREATMENT FOR HEPATITIS B,
TURNED OUT THAT HEPATITIS B
SURFACE -- WAS NOT AFFECTED WHEN
YOU GIVE -- BUT IT DID HAVE AN
EFFECT ON HDV.
SO THEN IT WAS PROPOSED AS
THERAPEUTIC.
IT'S A DAILY INJECTION AND THIS
IS THE ONLY DRUG THAT IS
APPROVED IN THE EUROPEAN UNION.
IT'S NOT APPROVED IN THE UNITED
STATES, IT IS APPROVED FOR
TREATMENT FOR HEPATITIS DELTA.
SO VIROLOGICAL RESPONSE, YOU SEE
THE DECLINE IN VIRAL LOAD,
COMPARED TO PLACEBO.
CLINICAL RESPONSE, NORMALIZATION
OF ALT, IN NEW ENGLAND JOURNAL
OF MEDICINE A COUPLE YEARS AGO
SHOWED THERE IS A COMBINED
RESPONSE, ABOUT HALF OF THE
PEOPLE WILL HAVE NORMALIZATION
OF ALT, AND END OF TREATMENT AT
48 WHILE THEY'RE RECEIVING THE
TREATMENT.
THE COMBINATION RESPONSE
TREATMENT, SUBSEQUENTLY THIS HAS
BEEN USED EXTENSIVELY IN EUROPE.
AND EUROPE HAS -- IT'S APPROVED
THERE AND PEOPLE HAVE BEEN
TREATING THIS IN EUROPE.
THIS IS A GOOD SUMMARY OF THE
DATA THAT'S HAPPENING AFTER ALL
LATER ON WITH THE PATIENTS
TREATED WITH THIS.
SO THREE DIFFERENT RESPONSES
HERE, IT A CROWDED SLIDE.
THE BLUE ONE IS THE PEOPLE WHO
HAVE LEVELS OF HDV RNA BELOW THE
LEVEL OF DETECTION.
LOOKING AT THE RED LINE IS THE
PEOPLE WITH HDV RNA MORE THAN
TWO LOG DROP.
AND THE GREEN ONE IS A COMBINED
RESPONSE THAT MEANS THEY HAVE A
2 LOG DROP AND NORMALIZATION OF
ALT.
AS YOU CAN SEE THIS DATA WOULD
SUGGEST THAT MOST OF THESE
PEOPLE HAVE ACHIEVED -- A LARGE
NUMBER OF PATIENTS HAVE 2 LOG
DROP EVEN IN REAL LIFE SCENARIO.
SO THAT'S BEEN WIDELY USED IN
EUROPEAN STUDIES AND MANY HAVE
STARTED -- IT CAN BE EXTENDED TO
96 WEEKS OF TREATMENT SO YOU'RE
TALKING ABOUT TWO YEARS OF
TREATMENT COMBINED WITH IT.
MANY OF THESE PEOPLE WILL HAVE
REBOUND EFFECTS WHEN YOU STOP
TREATMENT, BUT WHILE YOU'RE ON
TREATMENT, YOU CAN ACTUALLY HAVE
DECLINE IN VIRAL LOAD AS LESS
DECLINE IN NORMALIZATION OF ALT
SO YOU CAN HAVE NO PROGRESSION
OF FIBROSIS.
THE SECOND THERAPEUTIC -- ANDREW
WHO DISCOVERED THIS COMPOUND
COMPLAINS ABOUT THIS.
THIS IS A MOLECULE FOR A COMPANY
FROM CANADA WHO HAS THIS DRUG
DEVELOPED FOR MANY YEARS, FOR 20
YEARS AGO FOR HEPATITIS B.
-- EXACT MECHANISM IS NOT CLEAR
BUT NOW THERE IS MORE EVIDENCE
TO SUGGEST IT'S ACTUALLY
ASSEMBLED AND PACKAGED -- THESE
WERE THE MECHANISM OF ACTION, SO
AGAIN REDUCE THE VIRAL LOAD
GIVEN FOR THAT.
THE STUDIES WAS DONE IN
BANGLADESH AND MOLDOVA, B
SURFACE ANTIGEN AND
NORMALIZATION IN PATIENTS
TREATED EVEN SOME PEOPLE WITH
SEROCONVERSION.
THE PARTICULAR STUDY WENT BACK
AND LOOKED AT PEOPLE WHO HAVE
HEPATITIS D DELTA COINFECTION.
THESE ARE PATIENTS WHO ALSO HAD
DELTA.
YOU CAN SEE THE DELTA VIRAL LOAD
IS GOING DOWN ON ALMOST ALL OF
THOSE PATIENTS.
THEY IT NOT FOLLOW THE IMIEPED
RESPONSE BUT IT DOES HAVE
ACTIVITY AGAINST HEPATITIS DELTA
AS WELL.
THE THIRD ONE IS PROBABLY THE
MOST INTERESTING
MECHANISTICALLY.
THIS BLOCKS THE -- IT IS SAID
THE SMALL ANTIGEN BECOMES THE
LARGE ANTIGEN, AND THE
MODIFICATION IS PREVENTED.
THAT IS IMPORTANT BECAUSE A
LARGE MOLECULE, IT'S REQUIRED
FOR THE ASSEMBLY OF THE
HEPATITIS D DELTA, SO BLOCKING
THIS HAD GREAT FUNCTION.
MOST OF YOU KNOW HE'S APPROVED
ALREADY FOR PROGERIA.
THE MAIN CULPRIT OF AXILLARY
AGING UNDERGOES -- AND WILL LEAD
TO WORSENING OF CARDIOVASCULAR
MORTALITY SO IT'S ALREADY
APPROVED FOR THAT PARTICULAR
THING.
THIS IS A CROWDED SLIDE, THIS IS
A STUDY THAT LED TO MULTIPLE
DIFFERENT THINGS, MULTIPLE
DIFFERENT DOSES WERE TESTED,
MULTIPLE DURATIONED WERE TESTED.
IN THE STUDY OF RESULTS, IF YOU
LOOK AT 25 MG AND 50 MG DOSING
DOSING -- IT HAS POOR --
COMBINED WITH -- SO IT CAN
PROLONG THE CONCENTRATION OF
LOLONAFARNIB, SIMILAR TO YOU THT
HAVE TAKEN PAXLOVID FOR COVID.
YOU TAKE THIS, DO YOU THAT, THE
HIGHER DOSE DEFINITELY HAVE A
TWO LOG DECLINE AT THE END OF 24
WEEKS.
IF UP USE INTERFERON IN ADDITION
TO THAT, THEN YOU'RE ACTUALLY
HAVING ALMOST A 2.67 LOG DROP OF
ANTIVIRAL ACTIVITIES.
HIGHER DOSING, 50 MG DOSE,
YOU'RE GETTING CLOSE TO FOUR LOG
DROP IN 24 WEEKS.
IT IS A GOOD ANTIVIRAL AGENT
THAT HAS COMBINATIONS FOR THAT.
THE CONCERN IS THAT YOU HAVE TO
COMBINE WITH R -- DEFINITELY ISN
ORAL AGENT, IT HAS AN ADVANTAGE.
TO COMBINATIONS OF THAT, JUST TO
COMPARE THESE AGENTS WITH THE
THERAPEUTICS WE HAVE, LONAFARNIB
IS POTENTIALLY SHORT -- ALLOW
DAILY DOSING.
BUT DRUG AND DRUG INTERACTIONS
WITH -- IS A HUGE NIGHTMARE.
YOU CANNOT COMBINE THEM WITH
MANY OTHER MEDICATIONS AND FOR A
LONG PERIOD OF TIME FOR 24 WEEKS
IS DEFINITELY CONCERNING.
BUT IT ALSO -- MOST OF THESE
DRUGS HAVE NOT BEEN USED WITH --
PATIENTS SO YOU CANNOT REALLY
HAVE SAFETY DAY IT ON THAT,
CAN'T USE MEDICATION ON THAT.
SIDE EFFECTS ARE DEFINITELY
IMPORTANT.
GENERAL CONSIDERATIONS YOU CAN
USE -- STILL NEED TO DEFINE HOW
LONG YOU NEED TO TREAT TO CURE
HEPATITIS DELTA.
LONG TERM DATA IS NOT THERE.
INJECTABLE, SUBCUTANEOUS
INJECTABLE DAILY INJECTION, AND
THAT HAS GOOD TOLERABILITY IN
THE STUDIES BUT STILL AN
INJECTION.
TAKING PEOPLE WHO HAVE NO
SYMPTOMS AND GIVING THEM
INJECTION FOR A YEAR OR TWO
YEARS IS NOT GOING TO BE EASY TO
DO.
IT ALSO HAS NO SAFETY DATA ON
CIRRHOSIS PATIENTS AND TREATMENT
DURATIONS, WE DON'T REALLY HAVE
GOOD DAY IT ON WHAT HAPPENS
AFTER STOPPING TREATMENT FOR
SUSTAINED RESPONSE.
PEG INTERFERON ALPHA IS THE MOST
LONG TERM SPEENS, WE ALSO HAVE
GOOD DATA ON LONG TERM OUTCOMES
IMPROVEMENT WITH THE HEPATITIS
DELTA.
THE CONCERN WITH INTERFERON
ALPHA IS ALWAYS THE SIDE EFFECT
PROFILE.
IT HAS SIDE EFFECTS WHEN YOU
TAKE IT FOR A LONG PERIOD OF
TIME, IT BECOMES INTOLERABLE
MOST OF THE TIME.
PEG INTERFERON LAMBDA IS AN
OPTION, IT MAY HAVE SLIDELY
DIFFERENT SIDE EFFECTS BUT IT'S
ALSO NOT APPROVED FOFER FOR HEPS
DELTA.
TO SUMMARIZE, THERE ARE MULTIPLE
DIFFERENT STRATEGIES AVAILABLE.
THESE STRATEGIES LEAD TO
SIGNIFICANT DECLINE IN HDV.
IT IS NOT CLEAR WHETHER THIS
WILL LEAD TO FUNCTIONAL CURE.
PATIENTS HAVE TO GO OFF
TREATMENT AND THEN ONLY WE WILL
KNOW THAT THEY HAVE.
BUT THERE IS STILL AN ADVANTAGE
OF TREATING PATIENTS OF SUCH AN
AGGRESSIVE DISEASE AND ARRESTING
THE DISEASE WILL BE USEFUL FOR
MOST OF THESE PATIENTS.
MANY OF THESE STRATEGIES REQUIRE
ADDITIONAL ADDING PEG INTERFERON
WHICH -- LACK OF -- FOR
HEPATITIS B SO THERE'S ALWAYS
THIS THING IF YOU CAN CURE
HEPATITIS B YOU WON'T HAVE
HEPATITIS DELTA.
WE HAVE NOT MADE SUCCESS THERE
SO THAT'S REALLY NOT AN OPTION
BUT THAT IS DEFINITELY ONE OF
THE OPTIONS IF YOU HAVE A
METHODOLOGY TO -- OR A TREATMENT
PARADIGM THAT WILL CLEAR YOUR
HEPATITIS B.
CORRELATES OF CLEARANCE OF DELTA
ARE NOT CLEAR SO THAT'S ALSO
COMPLICATED, THAT HOW REALLY TO
DEFINE WHEN TO STOP TREATMENT
FOR THESE PATIENTS, IT'S NOT
VERY CLEARLY UNDERSTOOD, AND
THAT BECOME AS HUGE CHALLENGE IN
DECIDING CLINICAL TRIALS FOR
FUNCTIONAL CURE.
SO LOOKING AT THIS PARTICULAR
ASPECT OF IT, HOW WE UNDERSTAND
THE CORRELATES OF CURE FOR
HEPATITIS C ONE WAY WE TRY TO
UNDERSTAND IS TO DEVELOP
HUMANIZED MOUSE MODEL, SO
ACTUALLY HAVE -- IN
COLLABORATION, WE HAVE SEVERAL
OF THE YO HUMANIZED MOUSE MODELO
TAKE A MOUSE WITH LESS IMMUNITY
AND WE CONSIDER THE MOUSE WITH
HUMAN IMMUNE SYSTEM -- STEM
CELLS.
SO THAT REALLY COSTS THE IMMUNE
SYSTEM TO SOME EXTENT, AND -- SO
SLOWLY YOU CAN REPLACE THE MOUSE
LIVER WITH FETAL HUMAN LIVER.
WITH THIS, IT'S TRICKY, MOST
PEOPLE CANNOT DO, ONCE YOU HAVE
A HUMAN LIVER, YOU CAN INFECT
THEM WITH HEPATITIS B OR INFECT
THEM WITH HEPATITIS DELTA AND
DEVELOP CHRONIC DISEASE.
ANIMAL MODELS AS YOU ALL KNOW
HAS ISSUES WITH THAT.
SOME OF THE ADVANTAGES --
EASILY, QUICKLY, QUICKLY STUDY
THE EFFICACY OF VIRAL AGENTS BUT
IT DOESN'T REALLY TRANSLATE INTO
LONG TERM HUMAN MODEL, NOT
SIMILAR TO HUMAN WITH HEPATITIS
DELTA.
SO WE HAVE TO USE --
METHODOLOGIES TO MAKE THEM
DEVELOP CANCER AND THAT'S REALLY
NOT IDEAL.
SO LET'S GO AND FIND PEOPLE WHO
HAVE CLEAR HEPATITIS DELTA AND
FIND WHAT'S GOING ON IN THEM
IMMUNOLOGICALLY AND THEN WE'LL
UNDERSTAND -- INFORM OUR
UNDERSTANDING ABOUT WHAT
CORRELATES OF PROTECTIONS ARE
THERE.
SO WE WENT BACK TO MONGOLIA AND
FROM ANOTHER -- ONE OF MY
FELLOWS ACTUALLY WENT TO
MONGOLIA TO ESTABLISH A COHORT
THERE, ISTANBUL AND ALSO
PAKISTAN, AND WE GOT SAMPLES.
THIS IS PRIMARILY -- WE LOOKED
AT THREE GROUPS OF PEOPLE, THE
PEOPLE WHO HAVE BOTH CHRONIC
HEPATITIS B AND DELTA, CLEAR
DELTA ALONE BUT THEY HAVE
CHRONIC HEPATITIS B AND -- AND
THEY LOOK AT PHENOTYPING WHAT'S
DIFFERENT IN THE PHENOTYPING,
HEPATITIS B, HEPATITIS DELTA,
RNA, BULK RNA SEQ -- AS YOU KNOW
THE DIFFERENCE HERE IS MAINLY
THE ALT LEVELS, OTHERWISE THEY
ARE USUALLY MATCHED AND THEY'RE
NOT REALLY SIGNIFICANTLY
DIFFERENT FROM OTHER ASPECTS OF
IT.
SO JUST TO GIVE A BRIEF
HIGHLIGHT IS THAT ONE THING WE
FIND IS THAT THE CD8 CELLS
SUPPRESSING LOW LEVELS OF
INHIBITORY MOLECULES, AND
CTLA4 SIGNIFICANTLY REDUCED.
THEN PEOPLE WHO HAVE CHRONIC
HEPATITIS DELTA HAVE THESE
CD8 CELLS EXPRESSING THESE
INHIBITORY MOLECULES, PREVENTING
THEM FROM FUNCTIONING WHAT
THEY'RE SUPPOSED TO DO.
WHEN WE LOOK AT REPEAT
RESTIMULATION, WE TAKE BOTH
HEPATITIS B SPECIFIC AND D
SPECIFIC STIMULATION, THEN --
WITH HIV SPECIFIC PEPTIDES FOR
NINE DAYS, LOOK FOR ANTIVIRAL
CYTOKINES.
YOU SEE PEOPLE WHO CREATE
HEPATITIS DELTA MAKE MORE
CYTOKINES IN RESPONSE TO
STIMULATION WITH -- SPECIFIC
RESPONSE IS ACCELERATED.
THIS HAS BEEN SHOWN BY -- FOR
HEPATITIS B AND MANY OTHER DIES
DISEASE, HEPATITIS C, AS WELL AS
DEMONSTRATED MANY OTHER -- WHEN
YOU CLEAR YOU ALSO DEVELOP
IMMUNE RESPONSE AGAINST THAT
PARTICULAR VIRUS.
IT'S A CAUSE AND EFFECT,
SOMETHING DIFFICULT TO -- TNF
ALPHA PRODUCTION,
IL21 PRODUCTION.
WHEN WE LOOK AT WHETHER THEY
MAKE MULTIPLE CYTOKINES, THEY DO
ACTUALLY MAKE -- THEY MAKE
IL2 AND TNF, AND INTERFERON
GAMMA, THEY MAKE MULTIPLE
DIFFERENT CYTOKINES BUT --
GENERALLY WE BELIEVE THAT THE
CELLS MAKE MULTIPLE DIFFERENT
CYTOKINES BETTER EVEN THOUGH
THERE IS NO CLINICAL CORRELATION
THAT THIS ACTUALLY -- INTO ANY
KIND OF CLINICAL PARADIGM.
BULK RNA SEQ ALSO CLEARLY
DEMONSTRATED PATHWAYS THAT
IMPROVED T-CELL FUNCTION.
THOSE ARE THE PRIMARY PATHWAYS
IN THE PEOPLE WHO CLEAR DELTA --
OR THE TCR SIGNALING FUNCTION
AND HAS DECEL FUNCTION WAS THE
KEY SIGNATURE.
THAT LED US TO GO BACK AND LOOK
AT SINGLE CELL RNA -- WITH
DELTA, SPECIFICALLY CD8 CELLS,
THEN LOOK AT SOME -- I THINK
HERE -- THE PATHWAYS INCREASED
ANTIVIRAL GENES INCREASED T-CELL
RECEPTOR FUNCTION, AND REDUCTION
IN IMMUNOSUPPRESSIVE AND --
GENES.
SO THOSE OF MEES FUNCTIONS
CORRELATED WITH IMPROVED DELTA
SPECIFIC IMMUNOLOGICAL FUNCTION
AND RECOVERY FROM THE EFFECT OF
CHRONIC VIRAL EXHAUSTION AT D
CELL PHENOTYPE.
TO SUMMARIZE, RECUSED
EXHAUSTION, POLYFUNCTIONALITY,
PROLIFERATION, PRODUCTION OF
DIFFERENT CYTOKINES.
SO IN SUMMARY, GENE
SIGNATURES -- ENHANCE DE FACTO
MEMORY NEEN T PHENOTYPE -- IMPR-
CD4CD8 FUNCTION.
THE CHALLENGE IS THAT YES, THIS
IS A CROSS-SECTIONAL STUDY BUT
HOW DO YOU REALLY RELATE TO
IMMUNOLOGICAL END POINT TO GUIDE
TREATMENT?
IT'S VERY DIFFICULT TO DO.
BECAUSE THERE IS NO CUT POINT
LIKE A VIRAL LOAD, YOU CAN
ACTUALLY HAVE A DETECTABLE --
MUCH MORE DIFFICULT TO DO.
OUR NEXT STEP WOULD BE TO STUDY
IN THE CONTEXT OF TREATMENT OF
PATIENTS AND TRY TO VALIDATE
THAT WITH THE RESPONSE TO
CLINICAL OUT COME IN A
RESPECTIVE MANNER.
ONCE WE DO THAT WE CAN
DEVELOP -- THAT WILL HELP US TO
SAY -- AND YOU CAN ACTUALLY STOP
THE TREATMENT AND THEY WOULD BE
ABLE TO GET BETTER.
SO TO CONCLUDE THE SCREENING FOR
HEPATITIS DELTA IS NOT ROUTINELY
FOREMANNEDPERFORMED AND COULD PA
CHALLENGE WITH NEW PATIENTS.
THIS IS ONE OF THE REASONS WHY
THIS IS NOT APPROVED BY THE U.S.
FDA BECAUSE WE HAVE SO MANY
UNKNOWNS ABOUT DELTA PATIENTS IN
THE UNITED STATES.
WE DON'T REALLY HAVE A -- PCR
TESTING, WE DON'T KNOW THE
GENOTYPE DISTRIBUTION VERY WELL.
THERE'S SO MANY UNKNOWNS ABOUT
THIS.
SO WHO ARE THE PEOPLE HA ARE
GOING TO BENEFIT IS NOT KNOWN.
THIS DRUG WAS APPROVED IN THE
EUROPEAN UNION YEARS AGO.
THERE ARE SEVERAL THERAPEUTICS
COMING IN THAT WILL BLOCK HDV
REPLICATION AND HOPEFULLY THAT
WILL RELATE TO REDUCED DISEASE
PROGRESSION AND CARCINOGENESIS.
AND WE REALLY NEED A PREDICTIVE
ALGORITHM SO EFFICIENTLY WE CAN
BE LIKE HEPATITIS C, WHERE WE
HAVE A FUNCTIONAL KEURL PARADIGM
THAT CAN HAPPEN WITH THE
HEPATITIS DELTA, AND IT'S
DIFFICULT TO ACHIEVE BECAUSE OF
THE WAY THAT APPLICATION IS, BUT
THAT IS OUR ULTIMATE GOAL AND
HOPEFULLY AT SOME POINT, WE WILL
GET THIS.
I WANT TO ACKNOWLEDGE THESE,MOST
OF THE COHORT DEVELOPMENT HERE,
AND THE PEOPLE FROM MONGOLIA AND
TURKEY WHO PARTICIPATED IN THE
STUDIES AND THE PATIENTS.
THANK YOU, AND HAPPY TO TAKE
QUESTIONS.
[APPLAUSE]
>> THOSE WERE BOTH EXCELLENT
TALKS.
THANK YOU.
MY QUESTION IS AROUND NIH'S
RECENT PUSH TO MAXIMIZE
ORGANOIDS FOR RESEARCH FOR DRUG
DISCOVERY AND MOVING AWAY
FROM -- POTENTIALLY FROM ANIMAL
MODELS.
DO YOU FORESEE WITH LIVER
ORGANOIDS AND ARTIFICIAL
INTELLIGENCE, THIS IS A -- THIS
MAY BE AN OPTIMAL SCENARIO IN
TERMS OF DRUG DISCOVERY FOR
HEPATITIS D GIVEN THEY COULD BE
ORGANOIDS THAT COULD BE
DEVELOPED FROM PATIENTS WHO ARE
INFECTED WITH HEPATITIS DELTA
WITH DIFFERENT GENOTYPES AND TRY
MULTIPLE THERAPIES AT THE SAME
TIME?
>> IT A GOOD POINT -- ORGANOIDS
IS NOT A NEW FIELD, THERE ARE
SEVERAL DOING THAT, SO IT IS
DEFINITELY -- I JUST WANT TO
CLARIFY ONE POINT, THAT IT'S
VERY FOCUS ON ON THIR PEW TICK
DEVELOPMENT USING ORGANOID
SCREENINGS BUT A LOT OF WHAT WE
DO IS UNDERSTANDING -- FOR DRUG
DISCOVERY, YES, BUT THERE ARE
SORT OF LIMITATIONS, BUT THAT'S
ONE OF THE KEY ELEMENTS, WE
REALLY WANT TO UNDERSTAND THE
PROCESS OF CARCINOGENESIS, MUCH
MORE DIFFICULT TO DO IN THAT
KIND OF SETTING RATHER THAN IN
ANIMAL MODELS.
BUT USING ORGANOIDS IS NOT A NEW
THING, IT'S BEEN AROUND, YOU
COULD USE SCREENING PLATFORMS
VERY EASILY.
>> IF A MOTHER TRANSMITS
HEPATITIS D AS WELL AS HEPATITIS
B TO THE FETUS, HOW DOES THAT
INFLUENCE -- IF THAT HAPPENS,
HOW DOES THAT INFLUENCE THE
COURSE OF HEPATITIS D?
IT CERTAINLY IMPROVES AS THE
COURSE OF HEPATITIS B BUT HOW
ABOUT D?
>> SO I CAN GUESS ON THIS ONE
THAT USUALLY THEY WILL GET
CHRONIC DISEASE, BUT IF YOU HAVE
CHRONIC HEPATITIS B FROM THE
MOTHER, THERE IS HIGH LIKELIHOOD
THAT THE FEE CUSS CAN GET IT AND
THEY DEVELOP ALMOST 95% OF THOSE
FETUSES WILL GO ON TO DEVELOP
CHRONIC HEPATITIS B.
SO IF YOU GET BOTH AT THE SAME
TIME, THAT PARTICULAR GROUP OF
PEOPLE HAVE IMMUNITY SO THEY
CLEAR IT THEMSELVES.
DUSH -- IN THAT PARTICULAR SCE,
I'M NOT AWARE OF ANY LITERATURE.
>> ANOTHER QUESTION IS, IF
YOU'RE TREATING HEPATITIS C AND
A PERSON IS COINFECTED WITH
HEPATITIS B, AS YOU CONTROL THE
HEPATITIS C INFECTION, SOMETIMES
THE HEPATITIS B WILL REACTIVATE
AND SOMETIMES VERY SEVERELY.
SO IF THE PERSON IS COINFECTED
WITH D, DOES IT HAVE THE SAME
EFFECT ON B?
>> DID HOOFNAGLE ALWAYS
COMPLAINS ABOUT THIS, HE WROTE A
PAPER ABOUT THIS AND IT WAS
REJECTED MULTIPLE TIMES TO THE
EXTENT THAT HE NEVER ENDED UP
PUBLISHING IT AND WHAT HE SHOWED
WAS THAT IF YOU SUPPRESSED D
WITH INTERFERON, B WOULD FLARE.
AND YOU'RE CORRECT, THAT IS --
AND YOU WOULD THINK THAT
INTERFERON SHOULD SUPPRESS BOTH,
BUT HE ACTUALLY SHOWED THAT
THERE WAS THIS DANCE BETWEEN THE
TWO.
AND TO THE EXTENT THAT TODAY,
WHEN WE TREAT PATIENTS FOR
HEPATITIS D WITH INTERFERON, WE
OFTEN PUT THEM ON ORAL AGENTS TO
TREAT HEPATITIS B TO PREVENT
THOSE FLARES.
IT'S NOT THAT THEY DO BETTER.
I ACTUALLY THINK THEY MAY EVEN
DO A LITTLE BIT WORSE.
WE HAVE SOME EARLY EVIDENCE FOR
THAT, THAT IF YOU USE TENOFOVIR
AND -- TO TREAT HEPATITIS D, THE
D MIGHT BE EXACERBATED.
BUT WE DON'T WANT THEM TO HAVE
FLARES WHEN THE D GETS
SUPPRESSED.
IT'S A REAL ISSUE.
>> THAT SHOULD HELP US
UNDERSTAND THE MECHANISMS OF
INFECTION CONTROL, BUT HAVE WE
LEARNED ANYTHING FOR WHAT'S
GOING ON WHEN THAT ACTIVATION
OCCURS?
>> SO WITH COINFECTION --
USUALLY IT IS -- HEPATITIS C, B
IS LIKELY LOWER.
SO THE HYPOTHESIS AND JAKE HAS
DONE WORK IN HIS LAB ABOUT A LOT
OF THESE COMPETITION BETWEEN
HEPATITIS B, IT'S TUESDAY LISH
BEEN TWO VIRUSES COMPETING FOR
THE SAME HEPATOCYTE, ONE WINS
OUT, AND WHEN ONE IS GONE, IT
OPENS UP ALL THE OTHER OPENINGS
FOR THE NEW VIRUS THAT'S
ACTUALLY THERE IF IT'S NOT ON
TREATMENT, SUPPRESSIVE
TREATMENT, YOU CAN INVADE AND
GET A FLARE.
THAT'S THE COMMON SENSE ANSWER.
>> SO IT'S NOT A HOST EFFECT,
IT'S A COMPETITION FOR THE
HEPATOCYTE.
AT LEAST THAT'S THE THOUGHT.
>> AND NOT TO SPEAK FOR YOUR
WORK, BUT I THINK JAKE ALSO
SHOWED THERE'S CHANGE IN
INTERFERON WITH SUPPRESSION OF
ONE VIRUS ALLOWING THE SECOND
VIRUS TO FLARE.
BUT THAT WAS WITH HEPATITIS B
AND C, I THINK.
>> I WANT TO THANK BOTH OUR
SPEAKERS FOR YOUR TALKS.
I GUESS THE BAD NEWS TO SPRING
OFF YOUR STORY, CLEARLY YOU GUYS
DON'T KNOW ENOUGH BECAUSE
TOMORROW YOU'RE GOING TO GO BACK
TO YOUR LABORATORIES AND CLINICS
TO STUDY THIS VERY IMPORTANT
QUESTION.
SO THANK YOU VERY MUCH FOR
SHARING YOUR WORK WITH OUR
COMMUNITY.
THANKS, EVERYBODY.
HAVE A GREAT AFTERNOON, AND IF
ANYBODY WOULD LIKE TO SPEAK TO
THE SPEAKERS AFTERWARDS, PLEASE
DO SO.
THANK YOU VERY MUCH.
[APPLAUSE]