WELCOME TO CLINICAL CENTER GROUND ROUNDS. TODAY'S OUR CONTEMPORARY CLINICALIC MEDICINE GRADE TEACHERS WEEK. AND I HAVE THE SPECIAL PRIVILEGE OF INTRODUCING TODAY'S SPEAKER, HARVEY ALTER, WHO IS PERFOR THIS PRESENTATION WHICH COMES ON THE EVE OF OUR 60th ANNIVERSARY. OF THE CLINICAL CENTER. SO NOT HIS 60th ANNIVERSARY. OUR 60th ANNIVERSARY AT THE CLINICAL CENTER. [LAUGHTER] SO MANY OF YOU KNOW DR. ALTER. A BRIEF INTRODUCTION, ABINEFFICIENCY DISEASE RESEARCHER, A DISTINGUISHED NIH INVESTIGATOR. AND TRULY A PILLAR OF THIS COMMUNITY. CHIEF OF THE CLINICAL STUDIES AND ASSOCIATE DIRECTOR OF RESEARCH IN THE DEPARTMENT OF TRANSFUSION MEDICINE. AT THE CLINICAL CENTER. AS A YOUNG CLINICAL ASSOCIATE HERE AT THE NIH, IN THE EARLY 1960s, DR. ALTER HAD ONE OF THOSE ENCOUNTERS WITH DR. BLOOMBERG AND THEY JUST CO-DISCOVERED THE AUSTRALIA ANTIGEN KEY TO DETECTING HEPATITIS B. FOR MANY PEOPLE, THAT WOULD BE THE HIGH POINT IN THEIR CAREER. BUT NOT FOR DR. ALTER. THIS WAS JUST THE BEGINNING. AND I IMAGINE THAT THIS WAS THE BEGINNING THAT WAS TO BECOME MUCH MORE THAN ANY DREAMS HE EVER HAD OF WHAT HE MIGHT BECOME WHEN HE GOT OLDER. WAS GOING TO HAPPEN. DR. ALTER, AND HIS MEDICAL DEGREE AT THE UNIVERSITY OF ROCHESTER. I POINT OUT THIS YEAR HE'S DISTINGUISHED ALUMNIST OF THE YEAR FROM ROCHESTER. HE ALSO HAD SOME TRAINING AT THE UNIVERSITY HOSPITALS IN SEATTLE. CAME TO THE NIH CLINICAL CENTER AS A SENIOR INVESTIGATOR IN 1969 AFTER HAVING FINISHED HIS CLINICAL ASSOCIATE AND GOING TO GEORGETOWN AS WELL. IN 2000 RECEIVEED THE PRESTIGIS LASKER AWARD AWARD IN AND IN 2002 BECAME THE FIRST AND TO DATE THE ONLY CLINICAL CENTER SCIENTIST ELECTED TO THE NATIONAL ACADEMY OF SCIENTISTS. ALSO A MEMBER OF THE INSTITUTE OF MEDICINE. A MASTER OF THE AMERICAN COLLEGE OF PHYSICIANS. AND RECIPIENT OF THE KARL LUND STEINER AWARD THERE THE AMERICAN ASSOCIATION OF BLOOD BANKS, THE HIGHEST AWARD AND MANY OTHER HONORS. RECENTLY HE WAS SELECTED AS THE RESIP COULDN'T OF THE CANADA GARDENER INTERNATIONAL AWARD IN 2013. THIS AWARD WHICH WE PRESENTED IN TORONTO IN OCTOBER IS GIVEN TO INDIVIDUALS WHO HAVE DEMONSTRATED OUTSTANDING LEADERSHIP IN MEDICINE AND MEDICAL SCIENCE AND WHO'S WORK HAS CONTRIBUTED SIGNIFICANTLY TO IMPROVING THE QUALITY OF HUMAN LIFE AND THE HIGHEST AWARD THAT CANADA GIVES IN SCIENCE. AND TO DATE THERE ARE 313 AWARDEES FOR THIS AWARD, WHOM 80 HAVE GONE ON TO WIN THE NOBEL PRIZE. DR. ALTER'S LECTURE IS ENTITLED HEPATITIS C FROM HIPPOCRATES TO CURE. YEARS OF DEDICATION TO RESEARCH IN MEDICINE MAKE HIM A ROLE MODEL FOR ALL OF US. A MENTOR TO MANY, MANY YOUNG PEOPLE HERE AT THE CLINICAL CENTER. HARVEY, IT'S A PLEASURE. [APPLAUSE] THANK YOU. VERY NICE INTRODUCTIONS. YOU LEAVE ME SPEECHLESS. BUT NOT SO SPEECHLESS THAT I CAN'T TALK FOR 50 MINUTES. [LAUGHTER] NOW, I HAVE TO RUN THROUGH AN OBLIGGATARY SLIDE ABOUT FINANCIAL DISCLOSURE. I WILL TALK ABOUT TWO UNLICENSED DIRECT ACTING ANTIVIRALS BRIEFLY. I HAVE NO RELATIONSHIP WITH THE MANUFACTURE AND UNFORTUNATELY, NO FINANCIAL INTEREST IN THE DRUGS [LAUGHTER] NOW, THIS IS MY SECOND GREAT TEACHERS LECTURE. AND YOU MIGHT WONDER WHAT DOES THAT MEAN, TO BE GIVEN THIS LECTURE TWO TIMES? THERE ARE TWO HEALTH DISPARITIES. THE FIRST -- TWO HEALTH DISPARITIES -- [TECHNICAL DIFFICULTIES] HYPOCRISYIES. [LAUGHTER] I TAKE THIS AS A VOTE FOR THE SECOND ONE. I DO HAVE SOME FINANCIALS TO SHOW YOU. AS I SAID BEFORE, PEOPLE WORK AT NIH ONLY DREAM ABOUT HAVING FINANCIAL DISCLOSURES. BUT WAIT. THIS JUST IN. NIH HAS SEQUESTERED DREAMING. [LAUGHTER] BUT I DO HAVE SOME DISCLOSURES. MY LECTURE TODAY WILL INVOKE LINCOLN'S LAW OF LECTURING. WHICH IS THAT YOU CAN KEEP SOME OF THE AUDIENCE AWAKE ALL THE TIME, AND ALL OF THE AUDIENCE AWAKE SOME OF THE TIME. BUT YOU CAN'T KEEP ALL OF THE AUDIENCE AWAKE ALL OF THE TIME. AND I'M SURE I'LL PROVE THAT TODAY. SECONDLY, NOTHING I SAY REFLECTS THE POSITION OF THE U.S. GOVERNMENT. WHICH INSTANTLY GIVES A GREAT CREDIBILITY AND RELEVANCE. THIRD. MY MEMORY IS NOT AS SHARP AS IT USED TO BE. AND ALSO, MY MEMORY IS NOT AS SHARP AS IT USED TO BE. YOU'RE A GOOD AUDIENCE! [LAUGHTER] NOW, I DO HAVE REAL OBJECTIVES IN THIS LECTURE. FIRST, TO PLACE HEPATITIS C VIRUS IN HISTORICAL PERSPECTIVE. INCLUDING THE EVOLUTION FROM NON A NON B HEPATITIS. THE TRACE AND NEARER RADICATION OF POST TRANSFUSION HEPATITIS. TO DISCUSS THE PATHOGENESIS OF HCV INFECTION. TO SHOW THE OUTCOMES AND FOUNDERS, AND INCREASING THREAT OF HEPATOCELLULAR CARCINOMA. THAT WILL TAKE UP THE FIRST TEN MINUTES. MY MAIN OBJECTIVE IS TO GET PAST THIS LECTURE AND RETIRE BEFORE THEY REALIZE I'M ONLY A THIRD AS GOOD AS OTHER GREAT TEACHERS. AND THEY INVITE ME BACK FOR TRY. THIS IS A TIMELINE OF HEPATITIS HISTORY. THIS IS HIPPOCRATES, ONE OF THE TRULY GREAT TEACHERS, ONE OF THE GREAT LEADING HEPATOLOGISTS. AS YOU KNOW, HE GAVE US THE OATH, THE PHYSICIANS OATH, WHICH SAID PHYSICIANS FIRST DO NO HARM. AND THEN IT SAID SECOND, PHYSICIANS SECOND, GET PAID UP FRONT AND DO NOT EXCEPT MEDICARE [LAUGHTER] THAT MUCH HAPPENED OVER THE NEXT 2,000 YEARS. THERE WERE MANY WARS. AND EVERY WAR WAS COMPLICATED BY OUTBREAKS OF HEPATITIS, LARGE OUTBREAKS, WHICH WERE EITHER HEPATITIS A OR HEPATITIS B. THE B COMING FROM VACCINATIONS. BUT NOT MANY ADVANCES WERE MADE IN THE AREA OF HEPATITIS UNTIL THE 1960s WHEN JOHN HERE AT NIH, WE DISCOVERED THE AUSTRALIA ANTIGEN. FOUND THIS PECULIAR LINE IN AUGER AND IN TRACING OUT THIS LINE OVER THE YEARS, BLOOMBERG DEDUCED IT WAS RELATED TO THE HEPATITIS VIRUS. THIS GAVE US THE FIRST MARKER FOR ANY HEPATITIS VIRUS. I SCREWED THAT UP. WHOOPS. BUT THE KEY FOR US HERE IN THE CLINICAL CENTER WAS TO STUDY PATIENTS WHO WERE UNDERGOING OPEN START SURGERY. AND TO FOLLOW THEM PERSPECTIVELY WITH ALT MEASUREMENTS TO SEE HOW EMERGENCY PEOPLE WERE GETTING HEPATITIS. THESE STUDIES WERE STARTED IN THE 60s, JUST PRIOR TO MY COMING HERE. WERE DONE BY PAUL HOLLAND, PAUL SCHMIDT AND OTHERS, BOB PERCENTILE, PARTICULARLY. AND THEY SHOWED THAT THE HEPATITIS INCIDENCE HERE IN NIH WAS 33%. PRIOR TO 1970. ONE OUT OF EVERY THREE OPEN HEART SURGERY PATIENTS GOT HEPATITIS. A LOT OF BLOOD TRANSFUSIONS, HAPPY THE BLOOD WAS FOUND PAID DONOR SOURINGS THAT PROVE -- SOURCES THAT PROVED TO BE VERY RISKY. WHEN I CAME IN 1970 WE DECIDED WE COULD NOT TOLERATE THIS ANYMORE. WE WENT TO AN ALL VOLUNTEER DONOR SYSTEM AND INTRODUCED THE FIRST GENERATION TEST FOR HEPATITIS B. UNLICENSED ASSAYS. WE DID THEM OURSELVES. BUT THIS CAUSED A PERCRYPTIS FALL IN HEPATITIS INCIDENTS, 33% DOWN TO ABOUT 10%. SO THIS IS A PICTURE OF ME IN 1970. WEARING THE PUBLIC HEALTH SERVICE UNIFORM OF THE DAY. AS YOU CAN SEE, THE UNIFORMS HAVE CHANGED BUT I HAVE BASICALLY STAYED THE SAME. [LAUGHTER] NOW, IN 1973, THERE WAS A THIRD GENERATION TEST FOR HEPATITIS B AND WE WENT BACK TO THE STORAGE SAMPLES. AND MUCH TO OUR SURPRISE, WE FOUND THAT ONLY ABOUT 30% OF POST TRANSFUSION HEPATITIS WAS DUE TO THE HEPATITIS B VIRUS. THERE WAS OTHER ENTITY THAT WAS CALLED NON B HEPATITIS. IN 1975, ALSO HERE ON CAMPUS, FINE STONE ON THE RIGHT, AND OTHERS DISCOVERED THE HEPATITIS A VIRUS DISCOVERED THE SEAMAN'S ELECTRONIC MICROSCOPE STILL IN BUILDING 50. WHEN THEY DID THAT THESE WERE THE MAJOR COLLABORATORS, BOB PERSELL IN PARTICULAR. NOT A SINGLE ONE WAS DUE TO HEPATITIS A VIRUS. IT WAS DEDUCTIVE REASONABLE THAT WE SAID IF THESE WERE NOT DUE TO HEPATITIS A OR HEPATITIS B, WE WOULD CALL IT NON A, NON B. [LAUGHTER] NOW, WE DID THAT. WE THOUGHT OF CALLING IT HEPATITIS C AT THE TIME BUT WE HADN'T PROVEN IT WAS A VIRUS SO WE WERE CAUTIOUS. BUT WE WERE CONFIDENT WE WOULD FIND THE VIRUS VERY SOON, WHICH DIDN'T HAPPEN. BUT THE NEXT STEP IN THIS STORY WAS TO PROVE THAT THIS NON A NON B AGENT WAS TRANSMISSIBLE. FOR THAT, WE USED THE CHIMPANZEE MODEL. AS YOU CAN SEE, OUR CHIMPS WERE VERY EAGER TO BE IN THE STUDIES. THEY WERE TO LINE UP FOR INOCATIONS. WE INOCULATED THE FIRST FIVE AND ALL FIVE CAME DOWN WITH HISTOLOGIC AND TRANSSAM NASE HEPATITIS. THEY DIDN'T BECOME SICK. THREE CURVES ARE SHOWN ON THE RIGHT. THE IMPORTANT POINT, WE TRANSMITTED NOT JUST FROM PEOPLE, BUT FROM PEOPLE THAT HAD CHRONIC ASYMPTOMATIC HEPATITIS AND FROM PEOPLE WHO WERE ASYMPTOMATIC DONORS, SOME WHO HAD BEEN IMPLICATED IN HEPATITIS TRANSMISSION. WE KNEW THIS WAS A SILENT INFECTION THAT COULD BE BLOOD TRANSMITTED. THE NEXT THING IN THIS STORY WAS THIS PATIENT, WHO IS NOW DECREASED, BUT WAS PROBABLY THE SINGLE MOST IMPORTANT PATIENT IN THE HEPATITIS FIELD BECAUSE HE WAS STUDIED THROUGHOUT THE WORLD. HE LIKED TO CLIMB MOUNTAINS, NOT BIG MOUNTAINS BUT SMALL MOUNTAINS AND BLAZE TRAILS. HIS HISTORY IS HERE. IN 1968. HE HAD THE ONSET OF ANGINA, HAD A POSITIVE STRESS TEST. DIAGNOSED WITH HIPPER LIPIDEMIA. IN 1974 HE HAD CHANGES OF INFARCT. CLIMBING A MOUNTAIN IN 1976 HE LOST CONSCIOUS. HIS WIFE WAS WITH HIM, NEW CPR AND BROUGHT HIM BACK TO LIFE. IN 1977 HE WAS HERE AT NIH. HE HAD CARDIAC CATH, COMPLETE CORONARY OCCLUSION, AND TWO HIGH GRADE OCCLUSIONS OF OTHER VESSELS. IN MAY 25 HE HAD TRIPLE VESSEL BYPASS. AT THAT TIME WHEN THIS SURGERY WAS REALLY JUST COMING INTO VOGUE, HE WAS TRANSFUSED WITH 19 UNITS OF BLOOD. AND HE ENTERED INTO OUR PERSPECTIVE STUDY. SURE ENOUGH, IN JULY 12, ABOUT 8 WEEKS LATER, HE DEVELOPED HEPATITIS WITH SEVERE SYMPTOMS. HIGH BILIRUBIN LEVELS. ALT PEAK OVER 2,000. THIS IS HIS CLINICAL COURSE. AS YOU CAN SEE, SHOWN HERE IN BLUE, THE ALT ELEVATIONS STARTING AT ABOUT WEEK 6, ACTUALLY, IN YELLOW, OR THE RNA LEVELS DONE RETROSPECTIVELY. WE WERE FORTUNATE, ONE OF THE BETTER THINGS I DID, WE OBTAINED AND APHORESIS UNIT ON THE UPSWING OF HIS ALT CURVE. THAT MATERIAL WAS PUT INTO A CHIMPANZEE, SHOWN TO CAUSE HEPATITIS IN THE CHIMP. BOB PURCEL PERFORMED A TIGHTER IN OTHER CHIMPS AND SHOWED THAT THE TITRE IN THE CHIMP WAS ONE TIMES 10 TO THE 6.5, ALMOST IDENTICAL TO THE PEAK LEVEL VIREMIA IN THE PATIENT, 3 TIMES TEN TO THE 7. AT POINT B WHEN HE REACHED THE PEEK OF THE ALT ELEVATIONS WE INOCULATED CHIMP. NO LONGER INFECTIOUS. NOT SURE WHY THAT WAS, BUT WE KNOW THAT HIS VIREAMIC LEVEL WAS DESCREENEDING RAPIDLY AND HE HAD DEVELOPED ANTIBODIES SO MOST OF THE VIRUS WAS PROBABLY IMMUNE COMPLEX, THEREFORE, LEST INFECTIOUS. IN ANY EVENT, WE CAN SHOW THAT THERE WERE IMMUNE COMPLEXES. THE KEY WAS THAT WE NOW HAD A TITRED INFECTIOUS INOCKIUM AND HAD THE CHIMP MODEL. IF YOU HAVE THOSE TWO THINGS YOU CAN DO EXPERIMENTS. STEVE FINE-STONE TOOK THE SERUM AND HE DID THIS EXPERIMENT. WE DID CHLORFORM EXTRACTS OF THE SERUM WHICH WOULD DESTROY LIPPEDS. SHOWED IT WAS NOT INFECTIOUS IN THE CHIMP. THE SHAM EXTRACTED MATERIAL WAS INEFFICIENCY IN THE CHIMP. THIS IS A CRITICAL EXPERIMENT SHOWING THERE WAS AN ESSENTIAL LIPID THAT THE VIRUS WAS ENVELOPED AND THEVOLVE -- THE ENVELOPE. USED WITH FILTRATION TO SHOW THE SIZE OF THE VIRUS. 30-60 MANO METERS IN SIDE. IT HAD THIS ESSENTIAL LIPID ENVELOPE. THAT NARROWED THE FIELD OF POTENTIAL CANDIDATES DOWN TO EITHER THE SMALL RNA ALPHA VIEREROUSES, COULD HAVE BEEN A SMALL HEPATITIS B VIRUS. BUT WE HAD OTHER EVIDENCE THERE WAS NO RELATIONSHIP TO HEPATITIS B OR DELTA AGENT. OR IT COULD HAVE BEEN A NEW CLASS OF VIRAL AGENTS. AND DAN BRADLEY, CDC, WAS THE FIRST TO SAY THIS IS PROBABLY A FEDERAL RESERVEI VIRUSES AS IT TURNED OUT TO HAVE BEEN. WE KNEW THIS AGENT WAS SMALL. WE KNEW IT WAS PROBABLY A SMALL RNA VIRUS, MOST LIKELY IN THE FLAVI VIRUS FAMILY. WE KNEW IT WAS ASYMPTOMATIC, THE AGENT WAS TRANSMITTED BY BLOOD. WAS THE PRIMARY CAUSE OF TRANSFUSION ASSOCIATED HEPATITIS. AND THAT IT WAS TRANSMITTED NOT ONLY FROM ACUTELY INFECTED PATIENTS BUT FROM CHRONIC SILENT CARRIERS. WHAT WAS UNKNOWN WAS HOW SERIOUS WAS THIS DISEASE. PEOPLE QUESTIONED WHETHER THIS WAS REALLY AN IMPORTANT DISEASE. SO THEN WORKING WITH THE NIDDK LIVER SERVICE, WE BIOPSIED 39 OF THESE PATIENTS. FOUND THAT 10% HAS CIRRHOSIS AT THE TIME OF THE FIRST BIOPSY. 13% ADDITIONAL HAD SEVERE CHRONIC ACTIVE HEPATITIS. THAT WOULD EVIGNETTE IN CIRRHOSIS. FOLLOWED BIOPSIES IN 20 OF THESE PATIENTS, FOUND MANY IMPROVED, SEEMINGLY IMPROVED OR STABLE OVER TIME THAT 25% CONTINUE TO REGRESS. WE WOUND UP WITH 8 CASES OF CIRRHOSIS OR 20% OUT OF THE 39. AND THAT 20% CIRRHOSIS FIGURE HAS STOOD UP OVER TIME, ABOUT THE NUMBER OF PEOPLE WITH HEPATITIS C WHO DEVELOP CIRRHOSIS, 20-30%. BUT STRIKINGLY, SHOWN ON THE BOTTOM, IS THAT THREE OF THESE 8 PATIENTS DIED OF LIVER FAILURE. THREE HAD VERY SEVERE LIVER DISEASE WHILE THEY DIED OF SOMETHING ELSE. THIS WAS A VERY SIGNIFICANT DISEASE. NOW, I'M GOING TO TAKE SOME BREAKS TO TELL YOU WHAT IT TAKES TO BE A GREAT TEACHER. A GREAT TEACHER WILL STRETCH THE INTELLECTUAL LIMITS OF THE AUDIENCE BY RAISING DIFFICULT AND SOMETIMES IMPONDERABLE QUESTIONS. FOR INSTANCE, HE OR SHE MIGHT ASK, DO INFANTS HAVE AS MUCH FUN IN INFANCY AS ADULTS DO IN ADULTERY? [LAUGHTER] THIS IS STILL A DIFFICULT QUESTION. WE'LL GET BACK TO MORE OF THESE LATER. GOING BACK TO THE TRANSFUSION STORY, I LEFT YOU OFF HERE AROUND 75. BUT BY 1980, THE RATES OF HEPATITIS WERE DOWN TO ABOUT 5 TO 6% FOR A VARIETY OF REASONS. THE AMOUNT OF BLOOD TRANSFUSED WAS LESS. THAT CONTRIBUTED. SO WE DIDN'T START TO INTRODUCES OTHER MEASURES TO LOWER THE RATES OF HEPATITIS. WE TRIED TESTING DONORS FOR ALT. THAT DID NOT SEEM TO HAVE ANY BENEFIT. WHEN HIV CAME ALONG WE THOUGHT THIS MIGHT BE A GOOD SURROGATE MARKER FOR HEPATITIS. IT WASN'T. MOST OF THE HIV WAS TRANSMITTED BY MALES HAVING SEX WITH MALES RATHER THAN INTRAVENOUS DRUG USE. IN 1987 BASED ON RETROSPECTIVE ANALYSIS OF STORED SAMPLES AND FROM EACH STUDY, LOOKED LIKE ANTI-CORE TESTING, HEPATITIS B, MIGHT BE A GOOD SURROGATE FOR NON A AND NON B. AND THE RATES DROPPED. SO IT WAS ABOUT 1989 -- BECAUSE WE HAD WORKED VERY HARD, PARTICULARLY BOB PURCEL AND FELLOWS WHO DEFINED CHARACTERIZED THIS NON B NON A AGENT TO HAVE A TEST FOR IT. AND WE COULDN'T DO IT. SO BY 1989, I WAS QUITE FRUSTRATED. I WROTE A POEM CALLED" I CAN'T SEE THE FOREST FOR THE HBSAGs." I THINK I SHALL NEVER SEE THIS VIRUS CALLED NON A NON B. A VIRUS I CANNOT DELIVER, ALTHOUGH I KNOW IT'S IN THE LIVER. A VIRUS WE OFTEN BLAME, EXISTS ALONE BY NAME. NO ANTIGEN OR DNA, NO LITTLE TEST TO MARKETS WAY. A VIRUS IN OUR CONFUSION HAS FORCED US FINESSE COLLUSION, TO MAKE EXIST BY EXCLUSION. IS IT REAL OR ILLUSION. OH, GREAT LIVER IN THE SKY, SHOW US WHERE AND TELL US WHY. SEND US THOUGHTS THAT WILL INSPIRE US, LET US SEE THIS ELUSIVE VIRUS. IF WE DON'T PUBLISH SOON THEY'RE GOING TO FIRE US. [LAUGHTER] LET US FIND THIS LITTLE BEASTIE, GIVE US A SIGN, A STAR FROM THE EASTY. BUT JUST AT THAT POINT, MICHAEL AND HIS ASSOCIATES AT KRYON COOPERATION CLONED A NON B NON A. THEY HAD BEEN WORKING SECRETLY. YOU HAVE TO REMEMBER, THIS IS BACK IN THE 80s. MOLECULAR BIOLOGY WAS IN ITS INFANCY. AND THEY USED EXPRESSION CLONING, A NOVEL TECHNIQUE AT THE TIME. IT TOOK SERUM FROM INFECTED PATIENT. THEY EXTRACTED THE RNA. REVERSE TRANSCRIBED IT AND INSERTED IT INTO A GT11 EXPRESSION VECTOR. IF A VIRUS WAS THERE AND IF IT PRODUCED PROTEINS, THOSE PROTEINS WOULD BE EXPRESSED IN E. COLI WHO WERE INFECTED WITH THE PHAGE. THEY GREW THE E. COLI IN CULTURE. ANY PROTEINS WOULD CATCH ON TO AN ADHERENT FILTER PAPER. THEY MADE THE PREMISE THAT THERE MUST BE ANTIBIOTIC IN PATIENTS WHO HAVE NON B NON A HEPATITIS. NONE HAD EVER BEEN SHOWN, THIS WAS A TOTALLY BLIND STUDY. THEY WENT OVER 6 MILLION CLONES BEFORE THEY FOUND A SINGLE REACTIVE CLONE THAT REACTED WITH THIS ANTIBIOTIC. THEY WERE, THEN, ABLE TO LOCALIZE THE CONE, EXPAND IT, PRODUCE AN ANTIGEN TO FIND A GENOME AND DEVELOP AN ANTIBIOTIC ASSAY. IT WAS A REMARKABLE PIECE OF WORK THAT I THINK SHOULD GET THE NOBEL PRIZE. ONCE THEY HAD THE ASSAY THEY CAME BACK TO ME. WE HAD DEVELOPED A NON B NON A PANEL THAT WAS HIGHLY PEDIGREE, CONTAINED SAMPLES PROVEN INFECTIOUS IN THE CHIMP OR SAMPLES FROM DONOR WHOSE HAD PROVEN NOT TO INFECT PEOPLE AFTER TEN OR MORE DONATIONS. NOBODY HAD EVER BROKEN THAT PANEL. 19 LABS HAD CLAIMED A NON A NON B TEST. NONE HAD BEEN ABLE TO BREAK THE CODE. SO CRYON ASKED FOR THE PANEL. I SENT IT. THEY GAVE ME THE RESULTS BACK. I WAS EXPECTING ANOTHER FAILURE TRUTHFULLY. SO I WASN'T FAST GETTING THE RESULTS BACK TO THEM. AND CALLING AND CALLING ANXIOUSLY. ANYWAY, TURNED OUT THAT THEY BROKE THE CODE PERFECTLY. THEY PICKED UP THE THREE CHRONIC SAMPLES. IN EACH OF THE DUPLICATE SAMPLES. THEY PICKED UP 2 IMPLICATED DONORS. AGAIN, IN EACH OF THE DUPLICATE SAMPLES. THEY DID NOT PICK UP THE TWO ACUTE HEPATITIS CASES BECAUSE THEY WERE LOOKING FOR ANTIBIOTIC BUT LATER, THOSE TWO CASES SEARO CONVERTED FOR THE ANTIBODY. ALL THE PEDIGREED NEGATIVES WERE NEGATIVE. THEY DID 100%. I THEN TOOK OUT A 15 BEST NON B NON A CASES AND LOOKED FOR THIS ANTIBODY SERO CONVERSION. EVERY ONE OF THEM SERO CONVERTED. THEN LOOKED AT 25 CASES WHERE WE HAD DONOR SAMPLES. FOUND WE COULD DETECT AND POSITIVE DONOR IN 80% OF THE CASES. AND USING MORE SENSITIVE TESTS, ABOUT 88%. SO WE COULD PREDICT THAT TESTING DONORS FOR ANTI-HCV WOULD PREVENT 90% OF POST TRAN FUSION HEPATITIS. WHEN THAT WAS INPOLLUTIONS IN 1990 THE RATES OF HEPATITIS FELL FROM 4% DOWN TO 1.1%. BY 97. REACHED ZERO. THIS IS THAT SAME SLIDE WITH THIS DOWNWARD ARROW NOW. I SHOW THAT BECAUSE THIS SLIDE IS NOT JUST THE STORY OF POST TRANSFUSION HEPATITIS BUT THIS IS A STORY OF MY LIFE. AND BOTH POST TRANSFUSION HEPATITIS AND MY LIFE RUN THIS VERY RAPID DECLINE. AND I'M JUST EXTREMELY PLEASED THAT THE VIRUS SEEMS TO BE GONE AND I'M STILL HERE TALKING ABOUT IT. [LAUGHTER] WHAT IS THE IMPACT OF THIS TESTING? WELL, IF ONE TAKES THE INCIDENCE FIGURES THAT WE HAD DEVELOPED IN THE 1970s AND 1980s, AND MULTIPLIED THAT BY THE NUMBER OF TRANSFUSION RECIPIENTS, WE CALCULATE IN THOSE TWO DECADES THEY MIGHT HAVE BEEN NEAR 5 MILLION CASES OF POST TRANSFUSION HEPATITIS C. AND IF 20% GOT CIRRHOSIS, THAT WOULD BE 788,000 CASES OF CIRRHOSIS. IN THOSE TWO DECADES. NOT THAT MANY PEOPLE GOT CIRRHOSIS. THOSE PEOPLE OFTEN DIED OF OTHER DISEASES, HEART DISEASE FOR WHICH THEY WERE OPERATED ON. BUT THEORETICALLY THEY COULD HAVE GOTTEN -- WE DON'T KNOW THE REAL NUMBER. EVEN IF EVERYTHING IS HAVED OR A THIRD OF THESE NUMBERS, IT'S AN ENORMOUS NUMBER OF CASES TRANSMITTED. CONVERSELY, WHEN TESTING WAS INTRODUCED IN 1990, IF WE HAD NOT INTRODUCED THAT TEST. TIME WHEN THE RATES WERE 4%, THE 90s WOULD HAVE BROUGHT IN ANOTHER 1.2 MILLION CASES OF HEPATITIS. AND ANOTHER 192,000 CASES OF CIRRHOSIS. SO THESE THINGS HAD TREMENDOUS BENEFIT. NOW, BACK TO MY LESSONS. IMPORTANTLY, A GREAT TEACHER DOES NOT TELL ETHNIC JOKES. A GREAT TEACHER WOULD NOT TELL THE FOLLOWING STORY. A FRENCH PERSON SAYS I'M TIRED AND THIRSTY. I MUST HAVE WINE. A GERMAN PERSON SAYS I'M TIRED AND I'M THIRSTY, I MUST HAVE BEER. A JEWISH PERSON SAYS I'M TIRED AND I'M THIRSTY, I MUST HAVE DIABETES! [LAUGHTER] I'M GOING INTO HEPATITIS C NOW, NATURAL HISTORY. AND PERSISTENCE. CLASSICALLY, ABOUT 85% OF PATIENTS WITH HEPATITIS C DEVELOP PERSISTENT INFECTION. WE NOW THANK NUMBER IS -- THAT NUMBER IS LOWER, MAYBE 75-85%. 80%. INTELLIGENCE, MOST PATIENTS -- NONETHELESS, MOST PATIENTS DEVELOP PERSISTENT INFECTION. WHY? THE FIRST REASON, THIS VIRUS REPLICATES RAPIDLY, 13-17 HOURS DUPLICATING TIME. 1-2 WEEKS OF INFECTION YOU GO THROUGH A VERY RAPID UPSWING AND REACH THE ACTUAL VIRAL PEEK WITHIN TWO WEEKS. LEVELS THAT USUALLY TEN TO THE 5. TEN TO THE 18 COPIES. THE ALT LEVELS GOES UP MUCH LATER. ALT LEVEL GOES UP BECAUSE THAT'S THE TIME WHEN THE T CELL ATTACK ON THE LIVER. SO HERE THE T CELLS ARE COMING OUT, OUT HERE. BUT THE VIRUS IS EXPANDLING OVER HERE. BY THE TIME THE T SELLS ARE MOBILIZED, THEY HAVE TO FIGHT OFF THIS ENORMOUS VIRAL LOAD AND THEY BECOME OVERWHELMED. THEY BECOME BLUNTED IS THE EXPRESSION USED. SO THAT'S ONE REASON. THE SECOND REASON WAS ULUST DATED BY PATRICKA FOSTER. -- DONE BRILLIANT STUDIES. THE FIRST THING SHE DID WITH A LOT OF PATIENTS WAS TO LOOK FOR QUASI SPECIES EVOLUTION. THIS IS A SINGLE SAMPLE OF POINT OF TIME FROM THE PATIENT AND SHE DID 105 CLONES AND SEQUENCED THEM. AND 57% OF THE CLONES WERE IDENTICAL. BUT THE SAME TIME, 19 OTHER CLONES WERE ALREADY PRESENT IN THIS SERUM. SO EVEN IF HE MOUNTED A GOOD IMMUNE RESPONSE AGAINST THE DOMINANT CLONE, ANYONE OF THESE OTHER CLONES WAS ALREADY THERE AND READY TO TAKE OFF AND BECOME THE NEW DOMINANT CLONE. WE DID ANOTHER STUDY TAKING ONE OF OUR PATIENTS WHO HAD A RAPID PROGNOSIS FROM ONSET -- PROGRESSION FROM ONSET TO DEATH WITHIN 6 YEARS OF HEPATITIS C AND SAMPLED AT FOUR POINTS ALONG THE ALT CURVE. AND AT EACH POINT, SHE CLONED -- DID TEN CLONES SEQUENCED THEM. SO WEEK 3, THERE WERE 3 DOMINANT STRAINS. LABELED A, B AND C. BY WEEK 8, THOSE WERE NO LONGER DOMINANT. NOW STRAIN D WAS DOMINANT. ALSO EF AND G. WEEK 13, THINGS TOOK OFF. YOU COULD SEE THE A WAS STILL THERE, NOW THERE IS HIJK UP TO P. THE REASON FOR THIS INCREASED SPECIES EVOLUTION, ANTIBODY DEVELOPED IN BETWEEN THAT TIME, BETWEEN WEEK 8 AND 13. THAT ANTI-DROVE -- ATTACKS THE VIRAL ENVELOPE AND DROVE MORE VIRAL VARIATION. WEEK 16, THE REST OF THE ALPHABET WAS PLAYED OUT. IF SHE HAD DONE MORE CLONES THERE WOULD HAVE BEEN MORE VARIATION. SO THAT IS THE SECOND REASON. THE THIRD REASON, THE VIRAL PROTEINS AS I MENTIONED WERE INHIP TOGETHER TO THE T CELL RESPONSE. THIS IS USING A INTERFERON ASSAY, DONE IN DR. ROSEN'S LAB. SIMILAR WORK WITH BARBARA, WHO HAD DONE INCREDIBLE IMMUNOLOGY WITH HEPATITIS. IF YOU COMPARE HCG RECOVERED SUBJECTS, CHRONICALLY INFECTED PATIENTS, RECOVERED SUBJECTS MADE GOOD T CELL RESPONSES, THE:CALLY INFECTED PATIENTS HAVE VIRTUALLY NO RESPONSE. NO DIFFERENT THAN PEOPLE WHO HAVE NEVER BEEN EXPOSED TO HEPATITIS C. T CELLS ARE NOT WORKING EFFICIENTLY AGAINST THE VIRUS. THEY WORK AGAINST OTHER THINGS. OTHERS HAVE SHOWN THAT THE T SUPPRESSION CELLS, REGULATORY CELLS ARE INCREASED IN PATIENTS WITH CHRONIC HEPATITIS C AS OPPOSED TO THOSE WHO RECOVERED LIKE NORMAL PEOPLE. IF YOU PUT IT ALL TOGETHER -- THIS IS A VERY -- I APOLOGIZE, THIS IS VERY SHRIMPIC APPROACH. IF YOU LOOK AT THE HOST VIRUS INTO ACTIONS, THE VIRUS GETS THE EARLY LEAD REPLICATING RAPIDLY BEFORE THE IMMUNE RESPONSE. THEN IT GOES INTO THE EVOLVING QUASI SPECIES. THE VIRUS IS PRESENT IN HIGH LEVELS PRODUCING LOTS OF PROTEINS,STRUCT RECALL AND NON STRUCTURAL. MANY OF THESE PROTEINS SHOWN TO INHIBIT THE INNATE RESPONSE AT MANY LEVELS AND THE ADAPTIVE IMMUNE RESPONSE. NORMALLY, THE T -- GOOD RESPONSE, THESE T CELLS WOULD PRODUCE FAST LIGANDS, INTERFERON GAMMA THAT WOULD HELP TO GET RID OF THE VIRUS, TO NARROW THE SPECIES TOGETHER WITH ANTIBODY. GET NARROWED QUASI SPECIES AND YOU'D RECOVER IN 15-25%. BUT WHAT HAPPENS, ONCE YOU BLUNT THIS PIECE, THE ANTIBODY SERVES TO DRIVE THE EVOLUTION. YOU GET MORE VIRAL VARIANCE AND THEN YOU'RE INTO PERSISTENT INFECTION. NOW, A GREAT TEACHER WILL FULLY REVEAL THE ETHNICKICAL PRINCIPALS UPON WHICH THEY ARE GUIDED HAVE I THINK IT'S FAIR I TELL YOU MY GUIDING PRINCIPAL. THAT IS, I FEEL THAT TO STEAL FROM ONE IS PLAGIARISM, BUT TO STEAL FROM MANY IS RESEARCH. [LAUGHTER] THIS IS THE NATURAL HISTORY OF HEPATITIS C INFECTION. THE MAJORITY OF PATIENTS HAVE THIS VERY STABLE OR SLOWLY PROGRESSIVE COURSE, IN 60 TO 70%. 20 TO 30% HAVE A MORE SEVERE AND MORE RAPIDLY PROGRESSIVE COURSE. THEY WIND UP WITH CIRRHOSIS IN 15-40 YEARS, A SMALL PROPORTION HAVE A RAPIDLY PROGRESSIVE COURSE WHERE THEY DEVELOP CIRRHOSIS IN UNDER TEN YEARS, THIS HAPPENS MOST TRANSPLANT, THEY CAN GO TO SOAR ROSIS IN FIVE YEARS AFTER TRANSPLANT. THE MECHANISMS ARE NOT CLEAR. BUT IT'S HARD TO DISTINGUISH EARLY ON WHICH PATIENT IS GOING TO HAVE WHICH COURSE. THERE WERE NO REALLY GOOD PREDICTIVE MARKERS. THE VIREMIA LEVELS TEND TO BE THE SAME. THERE ARE SOME DIFFERENCES IN THE ALT PATTERN. IT'S NOT HIGHLY PREDICTIVE. THE DISEASE ONSET IS AT THE SAME TIME. SO IT'S BEEN DIFFICULT TO HAVE A PREDICTIVE MARKER. BUT MOST RECENTLY, PATRICE AND I HAVE TAKEN THE SAME PATIENTS, ONLY THREE PATIENTS FROM THIS GROUP, THREE FROM THAT GROUP, AND COMPARED CYTOKINE PROFILES AND OTHER THINGS. AND IMPORTANTLY, WHAT SHE SHOWED WAS THAT IN PATIENTS WHO HAVE THIS SLOWLY PROGRESSIVE COURSE SHOWN IN THE YELLOW, EARLY IN THE INFECTION THERE WAS VERY SIGNIFICANT VIRAL CONTAINMENT. THE VIRUS ALMOST GOES FROM HIGH LEVEL TO NEGATIVE. AND THEN THERE IS A BREAKTHROUGH. A BOTTLENECK AND BREAKTHROUGH. AND THE STRAIN BREAKS THROUGH AND REPLICATES AND THE VIRUS PERSISTS. ALMOST HAD A SPONTANEOUS RECOVERY. IN THE RAPIDLY PROGRESSIVE GROUP, THERE IS NO VIRAL CONTAINMENT AT ALL SUGGESTING THE IMMUNE RESPONSE IS NOT AS GOOD IN THAT GROUP. SECONDLY, SHE SHOWED IF YOU MEASURE PRO FIBROGENIC CYTOKINES, THAT THE SLOW PROGRESSES HAVE IF LEVELS OF INTERFERON GAMMA WHICH CAN CLEAR THE VIRUS, AND GOOD LEVELS OF MID POINT BETA COMPARED TO THE RAPID PROGRESSERS. MOST IMPORTANTLY SHOWED INTHE RAPID PROGRESSERS, FROM EARLY INFECTION ON THERE WAS A SIGNIFICANT INCREASE COMPARED TO THE SLOW PROGRESSERS IN MCP1. MONOCYTE CHEMO TACTIC PROTEIN, CALLED CCLT. THIS IS A CHEMO KIND THAT BOTH ATTRACTS STELLATE CELLS IN THE LIVER. THESE CELLS, THEN, PRODUCE COLLAGEN THAT LEADS TO FIBROSIS. SO WE WANT TO SEE NOW IF WE CAN VALID DATE THIS IN A LARGER NUMBER OF PATIENTS AND SEE THIS MIGHT BE A PREDICTIVE MARKER OF FIBROSIS. NOW, ONE MORE THING IS A GREAT TEACHER WILL EMPHASIZE THE IMPORTANCE OF EVIDENCE BASED MEDICINE, THIS IS A KEY WORD THESE DAY, SHOW BY EXAMPLE HOW THIS MODEL HAS INFLUENCED THEIR OWN THINKING. WELL, I HAVE BEEN GREATLY INFLUENCED. I'VE DONE AN EXPERIMENT, EVIDENCE BASED, STUDIED THE CHANCE OF A MAN WINNING AN ARGUMENT IN RELATIONSHIP VERSES THE TIME IN THAT RELATIONSHIP. AND I'VE SHOWN THIS. THAT DURING DATING ONE HAS ABOUT A 50% CHANCE OF WINNING AN ARGUMENT. ENGAGEMENT, ABOUT 25% CHANCE. AND ONCE MARRIED, THE GAME IS OVER. SO THIS IS EVIDENCE. I CAN TELL THIS FROM PERSONAL EXPERIENCE. [LAUGHTER] NOW, IN THE NATURAL HISTORY OF HCV INFECTION, A NICE EARLY STUDY WAS DONE BY TERRY IN FRANCE. IT WAS A FORWARD STUDY. HE TOOK PEOPLE WHO ALREADY HAD A GIVEN HISTOLOGIC OUTCOME AND TRACED BACK TO THEIR EXPOSURE WHICH WAS TRANSFUSION IN ALL THESE CASES. AND HE, THEN, SAID LET'S TAKE THE FIBROSIS STAGE, GOES FROM 0-4, DIVIDED BY THE DURATION OF THE INFECTION, THE TIME SINCE THE TRANSFUSION, AND CAME UP WITH AFRIN ROSIS UNIT WHICH IS 0.133 FIBROSIS UNITED STATES PER YEAR. EVERY 7.5 YEARS FROM STAGE -- UPPER STAGE. NOW, WHAT'S WRONG WITH THIS, IT SUGGESTS THAT HCV IS A LINEAR DISEASE. IT'S TRUE THAT AFTER 30 YEARS, ONE DOES OFTEN GET CIRRHOSIS. BUT MOST PATIENTS GET STUCK IN STAGE 0 OR 1 FOR DECADES AND DECADES. AND SO WHEN YOU DO THIS TYPE OF STUDY YOU GET A SKEWED PERSPECTIVE OF THE SEVERITY OF CHRONIC HEPATITIS C. THE TYPE OF STUDY YOU DO GREATLY INFLUENCES, META-ANALYSIS, GREATLY INFLUENCES WHAT YOU THINK IS THE OUTCOME OF THE INFECTION. SO THERE IS EVIDENCE THAT AT LEAST EARLY IN THE FIRST DECADE, THE INFECTION IS QUITE MILD. THIS IS OUR OWN STUDIES. WHERE WE LOOKED AT ASYMPTOMATIC BLOOD DONORS WE'RE STILL FOLLOWING. THIS IS ANALYSIS IN THIS GROUP OF 186 BIOPSIED PATIENTS. MEAN OF 25 YEARS SINCE THE EXPOSURE. EITHER BY INTRAVENOUS DRUG USE OR TRANSFUSION. YOU CAN SEE THAT MOST OF THE PATIENTS HAD NO FIBROSIS OR ONLY VERY MILD STAGE ONE FIBROSIS. 13% HAD BRIDGING. AND 2% HAD CIRRHOSIS. SEVERE OUTCOMES IN ABOUT 15% AFTER 25 YEARS. SIMILARLY, IN SEVERAL STUDIES OF WOMEN WHO RECEIVED CONTAMINATED LOTS OF RH IMMUNE GLOBULIN, THIS WAS A STUDY FROM GERMANY, 25 YEARS AFTER THE 490 WOMEN, YOU SEE THE HCV INFECTED IMMUNE GLOBULIN. THOSE THAT GOT INFECTED, 9% HAD BRIDGING FIBROSIS AND 2% HAD CIRRHOSIS. BAD OUTCOMES, LESS THAN 15%. THIS WAS A MULTIPLE CENTER STUDY HEADED BY LEONARD, WHERE THERE WERE 103 ANTIHCV POSITIVE PATIENTS. RECALLED IN 1987, 23 YEARS LATER. 77% STILL HAD ANTIBODY AND VIRUS, CHRONIC CARRIERS. 17% HAD ANTIBODY BUT NOT VIRUS. THESE WERE SPONTANEOUSLY RECOVERED SUBJECTS. AND INTERESTING, 7% NO LONGER HAD THE ANTIBODY. SO THEY HAD ALSO SPONTANEOUS RECOVERED. AND WE LOST ANTIBODY. THEY WOULD NEVER KNOW THEY HAD HEPATITIS C UNLESS YOU HAD THIS PRIOR SAMPLE. SO THIS MEANS THE RATE OF SPONTANEOUS RECOVERY IS ACTUALLY HIGHER AND PROBABLY CLOSER TO 25%. IN THIS STUDY, ONLY 15% OF PEOPLE HAD BAD HISTOLOGIC OUTCOMES AFTER 23 YEARS. SO EARLY ON, IT'S MILD. WHAT ABOUT LATER? WHAT'S GOING TO HAPPEN TO THESE PATIENTS LATER? ONE POSSIBILITY, WE KNOW THAT BY 20 YEARS, UNDER 20% HAVE PROBLEMS. IF THAT CURVE JUST PERSISTED AT THE SAME RATE, ABOUT 50% MIGHT HAVE CIRRHOSIS AFTER 60 OR SO YEARS. IT'S POSSIBLE THAT EVERYBODY WOULD DEVELOP CIRRHOSIS IF YOU JUST FOLLOW THEM LONG ENOUGH. BUT EVIDENCE OF THIS IS NOT THE CASE. IT'S ALSO POSSIBLE THAT IF YOU HAVEN'T EVOLVED GOOD FIBROSIS BY 20 YEARS, MAYBE YOU'RE A NON PROGRESSER. AND YOU'LL NOT DEVELOP CIRRHOSIS. THE ANSWER, I THINK, IS GOING TO BE IN HERE FROM OTHER OF THE STUDIES WE'VE HAD. BUT WE ARE CONCERNED THAT WITH TIME, AND WITH AGE, THAT WITH THE IMMUNOSUPPRESSION OF OLDER AGE, PEOPLE WILL DO WORSE OVER TIME. SO IN THE STUDIES JUST HAVEN'T GONE UP LONG ENOUGH TO PROVE THIS. SO THERE ARE CONFOUNDERS OF HCV INFECTION. AND ONE OF THE BIG ONES IS HIV OR OTHER IMMUNOSUPPRESSIVE STATES. IMMUNOSUPPRESSION DEFINITELY ACCELERATES FIBROSIS PROGRESSION. AS YOU CAN SEE BY THESE TWO CURVES, HIV POSITIVE VERSES NEGATIVE. AND IN THIS STUDY SHOWN THAT THE FIBROSIS CORRELATED WITH CD4 COUNTS, LESS THAN 400. IF IT WAS UNDER 200, YOUR RELEVANT RISK OF DEVELOPING CIRRHOSIS INCREASED TO 4. BUT MOST IMPORTANTLY, THE RISK OF DEATH FROM CIRRHOSIS IN THIS POPULATION WHEN THE CD4 COUNT WAS LESS THAN # HUNDRED -- 200, THE RELATIVE RISK WAS 11.9, COMPARABLE TO THE RISK OF HAVING HCV PLUS HEAVY DRINKING, 10.9. THIS IS ONE COMPOUND. MANY STUDIES HAVE SHOWN THAT ALCOHOL IS A CONFOUNDER OF HEPATITIS C OUTCOME. YOU CAN SEE AT EVERY TIME POINT, IF YOU HAVE HCV ALONE SHOWN IN RED, VERSES PLUS ALCOHOLISM, WHICH IS CAN FIND AS FOUR DRINKS A DAY FOR WOMEN, 6 FOR MEN, THIS IS CONSIDERED EXCESSIVE. YOU MAY HAVE DIFFERENT OPINIONS ON THAT. IN ANY POINT, THE RISK DOUBLES WHEN YOU GET OUT TO 30, 40 YEARS. THE RISK DOUBLES. IF YOU HAVE ALCOHOL IN ADDITION TO HCV. SO WE ALWAYS RECOMMEND TO OUR PATIENTS NOT TO DRINK. THOSE ARE THE GUIDELINES. NO DRINKING IF YOU HAVE CHRONIC HEPATITIS C BUT THE GUIDELINES ALSO SAY IF YOU DRINK, KEEP IT TO ONE DRINK A DAY. THIS IS WHAT WE ADVISE THE PATIENT. TWO PATIENTS WERE DOING PARTICULARLY BADLY. I SUSPECTED WERE DRINKING. THEY ALWAYS CLAIMS THEY WERE TAKING ONE DRINK A DAY. SO ONE DAY, I FOLLOWED THEM OUT AFTER CLINIC. THEY SEEMED TO COME TOGETHER. I FOLLOWED THEM AFTER CLINIC. THEY WERE TELLING THE TRUTH. THEY WERE HAVING ONLY ONE DRINK A DAY. [LAUGHTER] ANOTHER CONFOUNDER NOW IS OBESITY. THIS IS A DRAMATIC STUDY OF THE EFFECTS OF -- OR FATTY LIVER AND MORE SO, NON ALCOHOL -- NON ALCOHOLIC HEPATITIS. NASH. AND THIS IS FATTY LIVER WITH A METABOLIC SYNDROME. CHRONIC HEPATITIS C ALONE, THE RISK OF HAVING FIBROSIS AFTER 22 YEARS WAS ABOUT 16 YEARS. THIS IS SEVERE FIBROSIS. ABOUT THE SAME AS THE STUDIES I SHOWED YOU BEFORE. EVERYTHING IS VERY CONSISTENT IN THOSE FIRST 25 YEARS. BUT IF YOU HAD HEPATITIS C AND YOU ALSO HAD FATTY LIVER, THE RISK WENT UP TO 32%. THE RATE OF CIRRHOSIS. OR SIGNIFICANT FIBROSIS WENT UP TO 32%. IF YOU HAD FULL BLOWN NASH, INSULIN RESISTANCE, HYPER TENSION, FAT EELIER, THE RATE WENT UP TO 54%. THIS IS ALL A -- HEPATITIS C IS BEING VERY COMPLICATED BY OUR OBESITY EPIDEMIC. OBESITY EPIDEMIC AS YOU KNOW IS VERY DRAMATIC RIGHT NOW. SO DRAMATIC, DISPLAYED BY THIS PICTURE OF DAVID AFTER STAYING IN AMERICA, WHEN HE RETURNED TO ITALY, BEING IN AMERICA WITH QUITE THE RISK. [LAUGHTER] I WANT TO TALK ABOUT HEPATOCELLULAR CARCINOMA, QUITE AN IMPORTANT ENTITY RIGHT NOW IN HEPATITIS C. THIS DEPICTS THE PREVALENCE OF ANTI-HCV IN THE U.S. SHOWN IN BLUE. AGE PREVALENCE CURVE. VERSES JAPAN SHOWN IN YELLOW. WHAT YOU CAN SEE, IN JAPAN, THIS IS INFECTION OF THE ELDERLY. VERTICALLY NO NEW INFECTIONS ARE ENTERING THE POPULATION. THIS IS A COHORT EFFECT. THE DISEASE PROBABLY ENTERED THE JAPANESE POPULATION AT SOME POINT IN TIME AND NOW IT'S JUST BEING CARRIED FORWARD WITH THESE CHRONIC CARRIERS UNTIL SUCH TIME AS THEY DIE. IN THE U.S., IT'S DIFFERENT. THE PEAK IS AROUND AGE 40. AND THE IMPORTANT POINT OF THIS SLIDE IS THAT THERE IS A GAP IN AGE PREVALENCE BETWEEN U.S. AND JAPAN OF 30 TO 40 YEARS THIS IS IMPORTANT BECAUSE THE RATE OF HEPATOCELLULAR CARCINOMA IN JAPAN IS HIGHER THAN THE U.S. JAPANESE SAID THAT'S BECAUSE YOU HAVEN'T HAD THIS INFECTION AS LONG AS WE HAVE. WHEN YOUR POPULATION GETS TO BE THE AGE OF OUR POPULATION, YOU'LL SEE THE SAME RATES OF HEPATOCELLULAR CARCINOMA. WELL, WE DID A STUDY WITH JAPANESE COLLABORATORS. TWO DOCTORS, AND COMPARED -- DID A MOLECULAR CLOCK ANALYSIS. IT'S TOO COMPLICATED TO EXPLAIN, NOT BECAUSE I CAN'T EXPLAIN IT -- [LAUGHTER] BUT WHAT THIS DOES IS IT TELLS YOU WHEN A PARTICULAR GENOTYPE DIVERGED FROM COMMON ANCESTOR, AND WHEN IT BEGAN TO SPREAD RAPIDLY IN A POPULATION. SO IN JAPAN WHERE GENOTYPE 1B IS PREVALENT, IN DIVERGED AROUND 1880. THEN WAS QUIESCENT UNTIL THE MID 30s AND 40s WHEN IT BEGAN TO INCREASE AND SPREAD. WHAT WAS HAPPENING IN JAPAN AT THAT TIME? JAPAN WAS AT WAR. AT WAR FIRST WITH CHINA, THEN AT WAR WITH THE REST OF THE WORLD. WE NOW KNOW THAT NOT ONLY WERE THERE MASSIVE IMMUNIZATIONS, CONTAMINATED NEEDLES, SHARED NEEDLES, BUT THAT THE SOLDIERS FREQUENTLY SHOT UP WITH INFED MEANS PRIOR TO BATTLE. AND VIRTUALLY THE ENTIRE JAPANESE POPULATION OF MALES WAS IN THE MILITARY SERVICE. SO THAT WAS THE REASON FOR THE RAPID SPREAD OF HEPATITIS C IN JAPAN, NOW LEVELING OFF BECAUSE THEY DON'T HAVE THE DRUG EPIDEMIC OR NEEDLE SHARING. IN THE U.S., GENOTYPE 1A APPEARED AROUND 1910. BUT BEGAN TO SPREAD IN THE 60s AND 70s. WHEN WE HAD OUR OWN NEEDLE SHARING EPIDEMIC OF DRUG USE. AND UNFORTUNATELY, THAT IS NOT TAPERING IN THE U.S., DRUG USE CONTINUES AT A HIGH RATE. SO YOU SEE THAT AGAIN 30-40 YEAR GAP. I NOW BELIEVE THE JAPANESE THAT WE ARE IN FOR TROUBLE OVER TIME AND THAT'S ALREADY BEING SHOWN, IF YOU COMPARE THE LATE 70s WITH THE LATE 90s, THERE HAS BEEN A THREE FOLD RISE IN HEPATOCELLULAR CARCINOMA IN THE U.S. ALL DUE TO HEPATITIS C NOT TO OTHER CAUSES. AND INJECTED IF THERE IS NO CHANGE IN THE STANDARD OF CARE, THAT THE CASES OF DECOMPENSATED CIRRHOSIS AND HEPATOCELLULAR CARCINOMA, AND LIVER TRANSPLANTATION, GOING TO INCREASE ABOUT 4 FOLD OVER TEN TO 20 YEARS. FORTUNATELY, THE STANDARD OF CARE IS CHANGING. DRUG TREATMENTS HAVE GOTTEN MUCH BETTER. STARTING WITH INTERFERON ALONE. AND PROGRESSING TO RECENT THERAPIES WITH PEGINTERFERON. RIBAVIRIN FOR A YEAR. EFFECTED A 55% SUSTAINED VIRAL LOGIC RESPONSE, TANTAMOUNT TO A CURE. THAT HAS BEEN THE STANDARD OF THERAPY UNTIL RECENTLY. NOW THERE ARE NEW DIRECTED ACTING ANTIVIRALS, DRUGS THAT ARE HCV SPECIFIC, DESIGNER DRUGS JUST FOR THE VIRUS. THE FIRST CLASS OF THESE DRUGS ARE CALLED PROTEASE INHIBITORS. BUT THERE ARE MANY TARGETS. YOU COULD TARGET THE VIRUS AS IT ENTERS THE CELL. YOU COULD TARGET AS IT'S TRANSLATEED OR PROTEIN IS PROCESSED, OR AS IT REPLICATES OR ASSEMBLES OR EXCRETED. BUT THE FIRST GROUP OF DRUGS, THE PROTEASE INHIBITORS ARE AIMED AT THIS PART OF THE PROCESS. BUT NOW, THE UNLICENSED DRUGS IN CLINICAL TRIALS INCLUDE NS5B PRO LIMRAISE INHIBITORS. SO REPLICATION. AND NS5A INHIBITORS WHO'S EXACT ROLE IN THE REPLICATION CYCLE IS NOT KNOWN. BUT THESE TWO IN COMBINATION LOOK VERY EFFICACIOUS. SO WE'RE ENTERING NOW A STAGE WHERE -- FIRST, THIS IS JUST THE CURRENT THERAPY. WITH JUST THE PROTEASE INHIBITOR. IN THIS STUDY, THE RATES OF SUSTAINED RESPONSE WITH 4 WEEKS OF -- 24 WEEKS OF THERAPY WENT UP 44% WITH INTERFERON RIBAVIRIN TO 75% WITH THIS PROTEASE INHIBITOR, GIVEN FOR ONLY 12 WEEKS. YOU WENT UP AS HIGH AS 75%. BUT NOW WITH THE NEW DRUGS, THE -- HARD NAMES TO PRONOUNCE. THE NS5A INHIBITOR, THE NS5B INHIBITOR WHEN GIVEN FOR 24 WEEKS, THIS CASE WITH A ONE WEEK LEAD-IN FOR BOTH GENOTYPES 1 ALL THE WAY THROUGH 4, 93% CURE RATES AFTER 24 WEEKS. THIS IS NO INTERFERON, JUST ORAL THERAPY. IT'S DOWN TO ONE PILL A DAY. WHEN GIVEN JUST ALONG WITHOUT THE LESION, THERE WAS 100% CURE RATE. AND RIBAVIRIN ADDED TO THAT DIDN'T CHANGE THE 100%. SO THESE HAVE TO BE DONE IN MUCH LARGER NUMBERS OF PEOPLE ONGOING. PURCEL THESE ARE EXTREMELY ENCOURAGING RESULTS. I THOUGHT THEOMIGHT HAVE BEEN -- I DEVELOPED ACV SPECIFIC DRUG FOR JEWISH PATIENTS WHICH I CALLED ORVASIMIRE [LAUGHTER] SO LET'S SAY THIS AUDIENCE, LET'S SAY 100 IN THIS AUDIENCE THIS MORNING THAT YOU'RE STARBUCKS COFFEE WAS CONTAMINATED WITH HCV AND IT WAS ABSORBABLE THROUGH THE INTESTINE. OUT OF THIS 100 INFECTIONS, 20% ON AVERAGE WOULD HAVE A SPONTANEOUS RECOVERY. 80 WOULD DEVELOP A PERSISTENT INFECTION. OF THOSE 80, 30% WOULD HAVE A STABLE LOW GRADE NON PROGRESSIVE DISEASE USUALLY WITH NORMAL ALT LEVELS. 70% WOULD GO ON AND HAVE VARIABLE PROGRESSIONS. THOSE 56 PATIENTS WOULD TEND TO BE TREATED NOW SO IF THEY WERE TREATED NOW, THEY WOULD HAVE A 70% CURE RATE. SO 39 PATIENTS OUT OF THE 56 WOULD HAVE A SUSTAINED RESPONSE. 17 PATIENTS WOULD BE A TREATMENT FAILURE. SO OVERALL YOU'D HAVE 20 PATIENTS SPONTANEOUS RECOVERY, 24 DO WELL, PROBABLY WHETHER OR NOT YOU TREATED THEM. 39 WHO WERE TREATMENT CURES. SO YOU'D HAVE 83% FAVORRABLE OUTCOMES AND 17% SEVERE OUTCOMES. NOW, THE EFFICACY REALLY GOES UP TO 90%, THEN ONLY 6% WILL ULTIMATELY HAVE A SEVERE OUTCOME, IF YOU TREAT THEM. BUT THERE ARE CAVEAT -- THIS IS A WONDERFUL PICTURE. THIS IS NOT WHAT HAPPENS. SO THERE IT IS. CAVEATS AND PARADOX HERE. THE EFFICACY OF THESE TREATMENTS IS GOING TO BE VERY HIGH. MORE THAN HALF OF HCV CARRIERS ARE NOW UNIDENTIFIED. IN THE U.S. AND EVEN IF IDENTIFIED, MOST OF THESE PATIENTS DO NOT GET REFERRED FOR TREATMENT. THEY DON'T GET THE PROPER THERAPY. AND IF YOU GO TO THE DEVELOPING WORLD, TREATMENTS ARE NOT AVAILABLE. SO THIS IS AMAJOR PROBLEM IN DEVELOPING WORLD. BECAUSE OF THE VERY HIGH HCV GLOBAL PREVALENCE, 2% OF THE ENTIRE WORLD'S POPULATION IS INFECTED WITH HCV. THE ABSOLUTE NUMBER OF POTENTIAL DIRE EVENTS, CIRRHOSIS AND LIVER RELATED DEATH IS STAGGERING. MILLIONS AND MILLIONS. EVEN IF THE PROPORTION WHO DEVELOP THE EVENT IS RELATIVELY SMALL. SO BECAUSE IDENTIFICATION OF PATIENTS HAS BEEN DIFFICULT, THE CDC HAS COME UP WITH A NEW STRATEGY FOR TESTING. DOCTORS ARE AFRAID TO ASK QUESTIONS LIKE HAVE YOU EVER USED INTRAVENOUS DRUGS. THEY JUST DON'T ASK THOSE QUESTIONS. THE CDC HAS TRIED TO GET AWAY FROM ASKING THE QUESTIONS, AND FOLLOWINGSING IN ON -- FOCUSING IN ON THE BABY BOOMERS. BABY BOOMERS ARE PERSONS BORN AGAIN 1945 AND 1965. AND FOR SOME REASON, THESE PEOPLE ARE WILLING TO TRY ANYTHING. THEY LOVE TO SHARE WITH OTHERS. VERY GENEROUS PEOPLE. IN CALIFORNIA, THE BABY BOOMERS HAVE -- [LAUGHTER] REALLY BAD. THEY HAVE MADE SNORTING AND OLYMPIC EVENT. SO THE CDC IS TRYING TO GET AROUND THESE DELICATE QUESTIONS AND JUST SAYING LET'S IDENTIFY PEOPLE BY THEIR AGE WHEN THEY COME IN TO SEE A DOCTOR. RATHER THAN SPECIFIC EXPOSURES. AND THEN TEST AND TREAT THOSE WHO NEED TO BE TREATED. I THINK THIS WILL BE AN EFFECTIVE STRATEGY. IT STILL WON'T FIND EVERYBODY. SO AS I GET TO THE END, A GREAT, OLD TEACHER REALIZED THAT ONE CANNOT TEACH FOREVER. AND YOU HAVE TO LAY CONTINGENCY PLANS FOR THE FUTURE. GET A SECOND CAREER POST TEACHING. WELL I HAVE CHOSEN TO PURSUE A SECOND CAREER IN MUSIC. I'VE STARTED PRACTICING. [LAUGHTER] I THINK I CAN MAKE A GO OF THIS. AND -- BUT AT ALLLY, THERE ARE VIEW ADVANTAGES TO BEING OLD. ONE OF THEM IS THAT -- THIS IS EVIDENCE BASED. YOU REALLY DON'T GIVE A DAM. [APPLAUSE] I GOT TWO MINUTES TO END WITH A POEM. WHAT DOES IT MEAN TO BE A GREAT TEACHER? TO BE PART ACADEMIC AND PART A PREACHER? WHAT DOES IT MEAN TO COUNT OUT YOUR LIFE IN POWER POINTS, WHEN YOU COULD HAVE BEEN RESTING AT HOME SMOKING JOINTS. AND WHAT IF YOU'RE ONLY HALF A GREAT TEACHNER WHAT CAN THEY DO? CAN THEY INPEACH YOU? RELECTURE ON CUE, WE'RE IN HABITUAL CREATURE. OUR MOUTHS HAVE BECOME A DISTINGUISHING FEATURE. GREAT TEACHERS PROJECT WISDOM, LIKE SO CONSIDERTIES AND SPEW FORTH PRINCIPALS HIKE HIPPOCRATES. LOOKS LIKE WE ROCK WITH EASE, THAT WE HUM ALONG AND CLOCK DISEASE. SOMETIMES WE'RE GREAT, SOMETIMES WE'RE NOT. WHATEVER WE SAY, WILL SOON BE FORGOT. OUR STUDENTS HEADS WE'RE JUST A PASSING BLOCK, TEACHING FAME IS GREAT WHILE IT LASTS, IT'S JUST A SNAPSHOT. IN TRUTH, IT'S GREAT TO HAVE BEEN A MENTOR, TO HAVE BEEN ALLOWED OTHER PEOPLE'S MINDS TO ENTERED. I OMY CAREER AND SUCCESS TO THE CLINICAL CENTER. AND I'M VERY SAD THAT SOON I MUST FOLD UP MY TENTER. AND SO I HAVE JUST ONE LAST THING TO SAY, OLD TEACHERS NEVER DIE. THEY'RE JUST ERASED AWAY. THANK YOU. [APPLAUSE] >> IF ANYBODY WANTS TO ASK A QUESTION WE'LL TAKE ONE OR TWO. BUT OTHERWISE WHY DON'T WE JUST CHAT IN THE BACK? AFTERWARDS. THANK YOU.