>> GOOD AFTERNOON. WELCOME TO THE 17th ANNUAL ASTUTE CLINICIAN LECTURE. I'M JOHN GALLIN, DIRECTOR OF THE CLINICAL CENTER, IT'S A THRILL FOR ME TO INTRODUCE TODAY'S SPEAKER. DR. FRANCIS COLLINS HAD WANTED TO BE HERE BUT DUE TO PRESSING BUSINESS HE REGRETS HE COULD NOT BE HERE BUT HE SENDS HIS BEST WISHES. THE ASTUTE CLINICIAN LECTURE WAS ESTABLISHED IN 1998, THROUGH A GIFT FROM THE LATE DR. ROBERT W MILLER AND HIS WIFE, HIRUKU. MRS. MILLER REGRETS SHE COULD NOT BE ABLE TO ATTEND THIS AFTERNOON. THE SERIES HONORS A U.S. CLINICIAN SIGNIST WHO HAS OBSERVED AN UNUSUAL CLINICAL OCCURRENCE AND BY INVESTIGATING IT HAS OPENED AN IMPORTANT NEW AVENUE OF RESEARCH. OUR SPEAKER TODAY IS AN EXCELLENT EXAMPLE OF SUCH A PERSON. DR. JAY HOOFNAGLE IS THE SENIOR INVESTIGATOR IN THE INTRAMURAL LIVER DISEASES BRANCH AND DIRECTOR OF THE EXTRAMURAL LIVER DISEASES BRANCH IN THE DIVISION OF DIGESTIVE DISEASES AND NUTRITION AT THE NATIONAL INSTITUTE OF DIABETES AND KIDNEY DISEASE, AN EXPERT ON HEPATITIS, CIRRHOSIS AND OTHER DISEASES OF THE LIVER, EARNED HIS MEDICAL DEGREE AT YALE, RESIDENCY AT THE UNIVERSITY OF VIRGINIA HOSPITAL, A GASTROENTEROLOGY HEPATOLOGY FELLOWSHIP WASHINGTON. HE CAME TO NIH IN 1978, AS A SENIOR INVESTIGATOR IN THE INTRAMURAL LIVER DISEASES SECTION AT NIDDK AND FROM 1986 TO 1988 WAS THE ACTING CLINICAL DIRECTOR OF NIDDK AND IN 1988 BECAME THE DIRECTOR OF THE EXTRAMURAL DIVISION OF DIGESTIVE DISEASES AND NUTRITION IN THE SAME INSTITUTE. IN 2003, DR. HOOFNAGLE BECAME THE DIRECTOR OF THE NEW LIVER DISEASES RESEARCH BRANCH, AND HE CREATED THE LONG RANGE ACTION PLAN FOR LIVER DISEASES RESEARCH THAT IS STILL IN PLACE TODAY. HE'S A MEMBER AND FORMER PRESIDENT OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES. HE'S RECEIVED MANY IMPORTANT AWARDS FOR HIS RESEARCH, INCLUDING THE DISTINGUISHED ACHIEVEMENT AWARD FROM THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASE, THE GOLD MEDAL FOR LIVER DISEASE RESEARCH FROM THE CANADIAN LIVER FOUNDATION, AND A SPECIAL MEDAL FOR CONTRIBUTIONS TO GLOBAL HEALTH FROM THE UNIVERSITY OF PARIS. HE SERVED ON THE EDITORIAL BOARDS OF SEVERAL JOURNALS INCLUDING THE JOURNAL OF INFECTIOUS DISEASES AND ALMENTARY PHARMACOLOGY AND THERAPEUTIC. TODAY'S TALK IS "PAST AND FUTURE THERAPY OF HEPATITIS C." AND NOW, PLEASE WELCOME DR. HOOFNAGLE. [APPLAUSE] >> WELL, THANK YOU VERY MUCH. IT'S QUITE AN HONOR TO BE ABLE TO GIVE THIS LECTURESHIP AND BE CALLED AN ASTUTE CLINICIAN BY YOUR COLLEAGUES. I'VE BEEN CALLED A LOT OF THINGS, I'VE NEVER BEEN CALLED AN ASTUTE CLINICIAN. I'VE BEEN CALLED A KIND PHYSICIAN, AND I ACTUALLY USED TO BE CALLED HAND SOME PHYSICIAN IN MY YOUNGER YEARS, BUT ASTATE, NEW. I MADE THE FRONT PAGE OF THE NEW YORK TIMES AS EGREGIOUS PHYSICIAN. THAT'S ANOTHER STORY. WHAT I THOUGHT I WOULD DO IS TALK ABOUT PAST AND FUTURE OF THERAPIES OF HEPATITIS C BECAUSE THEY BEGAN IN THIS BUILDING. SO WHEN I CAME TO THE NIH FIRST IN 1972, AS A MEDICAL STAFF FELLOW, A STAFF FELLOW IN A VIRAL HEPATITIS LAB, IN 1972 THINGS WERE REAL SIMPLE. I USED TO THINK AS A MEDICAL STUDENT THE SIMPLE EXPLANATION WAS THE RIGHT EXPLANATION AND LEARNED THE HARD WAY, NO, THAT'S NOT TRUE AT ALL. IT'S USUALLY VERY COMPLEX. AND IT'S TRUE FOR HEPATITIS AS WELL. IN THOSE DAYS ONE DISEASE WAS A AND ONE WAS B, AND A WAS A VERY CONTAGIOUS DISEASE SPREAD BY THE FECAL/ORAL ROUTE, CAUSED EPIDEMICS, MOST PEOPLE RECOVERED. THERE WAS HEPATITIS B WHICH WAS AN ENDEMIC DISEASE, IT WASN'T VERY CONTAGIOUSU GET IT BY INJECTION DRUG USE, HIGH RISK SEXUAL BEHAVIOR BROOD TRANSFUSIONS. IT HAS A LONGER LATENCY AND CAN BECOME CHRONIC. THAT'S THE SIMPLE STORY, A AND B. THAT'S WHAT WE THOUGHT OF WHEN I STARTED. WHEN I STARTED WAS A PERIOD OF GROWTH IN HEPATITIS. THINGS WERE HAPPENING EVERY YEAR, NEW DISCOVERIES. BY 1972, THE AUSTRALIA ANTIGEN DISCOVERED IN THIS BUILDING AS WELL WAS CLEARLY LINKED TO HEPATITIS B AND RENAMED THE REPRESENT TIGHTS B SURPLUS ANTIGEN. THERE WERE IMPROVED TESTS FOR ANTIGEN AND ANTIBODY. MY LAB DESCRIBED THE CORE/ANTICORE SYSTEM, THE SWEDES DESCRIBED THE ANTIE SYSTEM, ALL COMING OUT IN THIS ONE YEAR. I WORKED IN THE FDA, IT WASN'T THE NIH AT THAT POINT, AND OUR LAB REQUIRED THAT ALL BLOOD IN AMERICA BE TESTED FOR HEPATITIS ANTIGEN AND IN 1972 WE REQUIRED THAT IT BE BY A THIRD GENERATION TEST, TRYING TO MAKE A REAL IMPACT INTO POST TRANSFUSION HEPATITIS, IT WAS BELIEVED TO BE HEPATITIS B. THE PROBLEM IS THAT POST TRANSFUSION HEPATITIS STILL OCCURRED, THE RATE DIDN'T GO DOWN A LOT. IT WENT DOWN 20, 25%. IF I HAD BEEN REAL ASTUTE I WOULD HAVE FIGURED IT OUT BUT I DIDN'T. THEN THIS VERY IMPORTANT DISCOVERY, IT WASN'T MADE IN THIS BUILDING BUT IF YOU HAD A ROCK YOU COULD HIT IT, BUILDING 7 OVER THERE. STEVE FEINSTONE DESCRIBED THE HEPATITIS A VIRUS USING IMMUNE ELECTRON MICROSCOPY, USED BY AL KAPIKIAN TO DISCOVERED THE NOR WALK AGENT, WITH SERIAL STOOL SPECIMENS FROM PATIENT WITH HEPATITIS A AND USED CONVALESCENT SERUM AND ANTIBODY AND SHOWED IMMUNE COMPLEXES IN THE STOOL, THE FIRST STEP TO DISCOVERING HEPATITIS B, THE FIRST STEP TO DEVELOPING TESTS FOR HEPATITIS A AND DEVELOPING THE VACCINE AND NOW IN AMERICA HEPATITIS A IS AN UNCOMMON DISEASE, THE RATE HAS FALLEN 90% BECAUSE OF THIS DISCOVERY SO LONG AGO. BUT IMPORTANT DISCOVERIES IN MEDICINE AND SCIENCE NOT ONLY ARE GREAT FOR THE QUESTIONS THEY ANSWER BUT ALSO FOR THE QUESTIONS THEY RAISE. AND WHAT WAS IMPORTANT IN THIS DISCOVERY WAS NOT ONLY WHAT THEY FOUND BUT WHAT THEY DIDN'T FIND. WHAT THEY DIDN'T FIND WAS THAT HEPATITIS A WAS NOT A CAUSE OF POST TRANSFUSION HEPATITIS. I MEAN, LIKE NONE. ZERO. THEY WERE ALL, NEITHER A NOR B. AND IT WAS CLEAR TO ALL OF US THEN THAT THERE WAS A THIRD FORM OF VIRAL HEPATITIS. IT DIDN'T HAVE A NAME. IT WAS CALLED NONA, NONB. BUT YOU DON'T WANT TO HAVE A DISEASE THAT DOESN'T HAVE A NAME, OKAY? IT'S ALWAYS UNSATISFACTORY TO HAVE A "NON" IN THE NAME OF THE DISEASE LIKE NONINSULIN DEPENDENT DIABETES. TYPE 2 SOUNDS SO MUCH BETTER, RIGHT? NON-A, NON-B WAS APPROPRIATE BECAUSE WE DIDN'T KNOW WHAT THE VIRUS WAS. WE USED ALL THE METHODS USED IN HEPATITIS B, IMKNEW DIFFUSION, COMPLEMENT FIXATION, RADIOIMMUNOASSAY, FLUORESCENCE MICROSCOPY. I SPENT HOURS LOOKING AT ELECTRON MICROSCOPES. MY EYES ARE STILL WEAK FROM ALL THAT. DIDN'T SEE ANYTHING. CELL CULTURE, CHIMPANZEE TRANSMISSION STUDIES. AND THEN ULTIMATELY NEW MOLECULAR TECHNIQUES. AND IT'S THE END OF THE SLIDE THAT'S THE SUCCESS STARTED COMING. THE DISEASE WAS TRANSISSIBLE TO CHIMPANZEES AND IT WAS A VIRUS, AND THEY COULD FIND CHIMPANZEE SERUM WITH HIGH LEVELS OF VIRUS IN IT. WHY CAN'T WE FIND IT? WHY CAN'T YOU SEE IT? WELL, EVEN IN THE 1980s WAS GETTING VERY FRUSTRATING, IF I HAD A STAFF FELLOW WHO I REALLY HATED, I COULD PUT HIM TO WORK ON FINDING NON-A, NON-B HEPATITIS BECAUSE YOU COULDN'T FIND ANYTHING. YET WE BEGAN TO UNDERSTAND THE DISEASE, COULD FIGURE OUT WHO HAD IT. THE CHARACTERISTICS WERE DEFINED ACTUALLY. IT WAS A COMMON CAUSE OF POST TRANSFUSION HEPATITIS. AT THAT POINT IT SEEMED TO ACCOUNT FOR ALL CASES, IT WASN'T CLEAR WHETHER IT WAS ONE VIRUS OR TWO. SOME ADVOCATES FOR TWO. IT CAUSED BOTH ACUTE AND CHRONIC HEPATITIS EFFECT, THE CHRONICITY SEEMED TO BE VERY HIGH, AND IT LOOKED LIKE IT WAS AT LEAST 50%. ULTIMATELY, IT WAS SHOWN TO BE 80%. IT APPEARED OCCASIONALLY CAUSE CHRONIC HEPATITIS THAT COULD LEAD TO CIRRHOSIS AND ULTIMATELY SHOWN THIS RANKS WITH ALCOHOL AS THE MOST COMMON CAUSE OF CIRRHOSIS IN THE WESTERN WORLD. AND IT COULD CAUSE LIVER CANCER OCCASIONALLY, IT SEEMED TO. NOW IT'S CLEAR THAT HEPATITIS C IS PROBABLY THE MAIN CAUSE OF CANCER OF THE LIVER IN AMERICA. WELL, AS FRUSTRATING, AND WHAT ABOUT THERAPY, SEEING THESE PATIENTS WE THOUGHT WE CAN JUST TRY. SO WE TRIED DESPITE THE LACK OF SEROLOGIC AND VIRAL MARKERS. THERAPY WAS ATTEMPTED. CORTICOSTEROIDS WE TRIED. CLEARLY THEY WERE HARMFUL. TRIED ACYCLOVIR, GAVE IT IV EVEN, HAD ABSOLUTELY NO EFFECT. WELL, INTERFERON WAS AN OBVIOUS CHOICE BUT IT WASN'T AVAILABLE UNTIL THE EARLY 1980s WHEN RECOMBINANT INTERFERON WAS MADE AND USED EXPERIMENTAL. WHY USE INTERFERON? IT MAKES SENSE. BROAD SPECTRUM OF ANTIVIRAL ACTIVITIES, ACTIVITY IN VITRO, SO CULTURE AGAINST VIRTUALLY EVERY VIRUS, THERE'S SOME SYSTEMS YOU CAN SHOW INHIBITION, REGARDLESS IF ITS RNA OR DNA. WE HAD BEEN USING IT IN HEPATITIS B AND AN EFFECT IN D AS WELL. THIS IS WHAT WE USED IN B, A FOUR-MONTH COURSE WHICH INDUCED REMISSION IN A THIRD OF PATIENTS WITH HEPATITIS B. WE KNEW ITS SIDE EFFECTS, EFFECTIVE DOSE, WE KNEW DURATION OF TREATMENT FOR HEPATITIS B AT LEAST, SO IN 1982 I GOT IRB APPROVAL TO TREAT A SMALL NUMBER OF PATIENTS WITH NON-A, NON-B HEPATITIS WITH INTERFERON. THEY HAD CLEAR RISK FACTORS AND ELEVATED ENZYMES, ALWAYS HIGH, NEVER NORMAL, LIVER BIOPSY, WE A PLANNED TO TREAT, THE END POINTS WITH CHANGE IN ALT LEVELS AND LIVER HISTOLOGY, SOUGHT INDUSTRY SUPPORT FROM THREE COMPANIES. SCHERING-PLOUGH WAS WILLING TO DO IT. THEY USED INTERFERON IN THE COLD AND THEY AGREED. HERE IS WHAT HAPPENS AM FOUR-MONTH COURSE OF INTERFERON, AND WE HAVE ALL KINDS OF NICE MARKERS FOR HEPATITIS B, DNA AND ALL, AND HERE IS THE ALT LEVELS. LOOK WHAT HAPPENS WITH HEPATITIS B. THE DISEASE FLARES WHEN YOU TREAT WITH INTERFERON. AND THEN WHILE THEY ARE ON TREATMENT, AND THEN KIND OF AS YOU TAKE THEM OFF, THEY GET BETTER, AND THEY GO INTO REMISSION. THEY CAN CLEAR THESE VIRUS MARKERS. THIS PATIENT EVEN TWO YEARS LATER BECAME NEGATIVE FOR HEPATITIS ANTIGEN, SO THIS IS WHAT WE WERE HOPING TO SEE, MAYBE SOMETHING LIKE THIS IN HEPATITIS, NON-A, NON-B BUT THIS IS WHAT WE SAW. THIS IS ACTUALLY PATIENT NUMBER THREE. BUT HE WAS A TURNING POINT IN OUR THINKING. HE HAD ELEVATED ENZYMES ALL THE TIME AS A YOUNG MAN. DIDN'T HAVE ANY SYMPTOMS BUT HIS ALT WAS VERY HIGH, IN THE 300s. AND I BOTHERED HIM FOR A YEAR, WAS NEVER BELOW 300. I FOLLOWED HIM FOR A YEAR. WE PUT HIM ON INTERFERON AT THE DOSE FOR HEPATITIS B AND IT WAS NORMAL. I THOUGHT IT WAS A LAB ERROR. SOMETHING HAPPENED. NOW, IN OUR STUDIES, THIS STUDY AND FUTURE STUDIES, WE NOT ONLY STUDY EFFECT OF THE DRUG BUT THE EFFECT OF TAKING THE PATIENT OFF THE DRUG. THAT'S VERY IMPORTANT. THE OFF RESPONSE. THIS IS THE ON RESPONSE. WHAT ABOUT THE OFF RESPONSE? WELL, WE DON'T HAVE ANY VIRAL MARKERS TO FOLLOW HERE, JUST THE ALT. SO THIS IS THE SAME PATIENT. THERE HE IS, WE STOPPED AND HE RELAPSES AND ACTUALLY HIS ALT TWO MONTHS LATER IS EXACTLY THE SAME, WENT RIGHT BACK TO WHERE HE WAS BEFORE. SO WE STARTED AGAIN, AND THIS TIME WHAT I DID WAS LEFT HIM ON FOR A YEAR AND GRADUALLY LOWERING DOSES, ALT REMAINED NORMAL, NORMAL, NORMAL. YOU CAN'T SEE IT HERE BUT WE STOPPED. AND SIX MONTHS LATER IT REMAINED NORMAL. THE LIVER BIOPSY GOT BETTER TWO SO WE HAD TWO MARKERS, LOOKED LIKE HE WAS BETTER. WELL, WE ULTIMATELY TREATED TEN PATIENTS. ALL HAD STABLE PERSISTENT ELEVATIONS OF ALT BEFOREHAND AND ALT FELL TO NORMAL IN EIGHT DURING TREATMENT. IMPORTANTLY, THEY REMAINED NORMAL AFTER THERAPY, THREE RELAPSED AND THEN FIVE, SO HALF THE PATIENTS, ALT REMAINED NORMAL EVEN AFTER WE STOPPED. WE PUBLISHED THAT PAPER. MEANWHILE SCHERING GOT AN INTEREST IN WHAT I WAS DOING, SO WE -- THAT WAS A PILOT STUDY WE EMBARKED ON A CONTROLLED TRIAL. WE PROBABLY MADE MISTAKES BUT WE MADE MISTAKES BECAUSE THEY WERE IN SUCH A HURRY. TWO STUDIES WERE DONE. ONE WAS A US MULTI-CENTER TRIAL SPONSORED BY SCHERING, AND ONE IN THE CLINICAL CENTER WHERE WE GAVE VARYING DOSES THREE TIMES A WEEK, TWO MILLION AND SCHERING BRACKETED WHERE WE DID WITH THREE MILLION AND ONE MILLION. WE HAD A PLACEBO CONTROL GROUP, THE FIRST AND LAST TRIAL OF PLACEBO CONTROLLED TRIAL OF INTERFERON DONE IN THE UNITED STATES. IT WAS VERY DIFFICULT. THAT WAS ONE REASON WE DID A STUDY FOR SIX MONTHS RATHER THAN LONGER. AND THESE ARE THE RESULTS, UNCOMMON IN THE PLACEBO OR UNTREATED. THERE ARE TWO THINGS WRONG. FIRST OF ALL, IT SAYS HERE ALT ON THERAPY. THIS IS THE END OF TREATMENT ALT RESULTS. NOT AFTER STOPPING. THEY WERE IN TOO MUCH OF A RUSH TO PUBLISH IN THE NEW ENGLAND JOURNAL OF MEDICINE. THE OTHER THING IS THE DOSES WERE NOT DIVERSE ENOUGH, THIS IS WHAT WE DID. THAT WAS 1989. IN THE MEANTIME THIS BREAKTHROUGH WAS MADE, A LANDMARK BREAKTHROUGH IN THE 20th CENTURY MEDICINE, DISCOVERY OF THE HEPATITIS C VIRUS, IDENTIFICATION OF SMALL VIRAL RNA IN SERUM, ALLOWED FOR DEVELOPMENT OF TEST, RAPIDLY INTRODUCED INTO BLOOD BANKING, BLOOD DONOR SCREENING, ALLOWED FOR ACCURATE DIAGNOSIS NOW, AND LED TO THE ELUCIDATION OF THE STRUCTURE OF THE HEPATITIS C VIRUS, VERY IMPORTANT. TESTS FOR THE VIRUS AND SERUM, EVEN WITH DISCOVERY, YOU COULD NOT DETECT THE VIRUS USING DIRECT HYBRIDIZATION. THE RNA WAS NOT ENOUGH, OR WHATEVER. I DON'T KNOW WHY. BUT WITH PCR YOU COULD. IT TOOK A LOT OF BREAKTHROUGHS IN MOLECULAR MEDICINE, THIS WAS BASICALLY -- THEY EXTRACTED RNA, REVERSE TRANSCRIPTION AND FINALLY E. COLI AND EXPRESSION CLONING SCREENING THE BACTERIA FOR EXPRESSION OF ANTIGEN USING CONVALESCENT SERUM, A VERY ELEGANT AND NICE METHOD. THAT WAS IT. OKAY. EVERYTHING STARTS TO GET CLEAR HERE. HEPATITIS C VIRUS, WE KNEW THE SIZE OF IT ALREADY. 60 LAMBDA. AND WE KNEW IT WAS ENVELOPED, BUT THIS IS WHAT IT LOOKS LIKE, ENVELOPE VIRUS WITH A NUCLEOCAPSID SCORE, INSIDE SINGLE STRAND OF POSITIVE POLARITY RNA. THE STRUCTURE OF RNA WAS WORKED OUT BY THE CHYRON GROUP AS WELL AS OTHERS, IT HAS THE STRUCTURAL PROTEINS ON THE PRIME END, AND NONSTRUCTURAL ON THE THREE-PRIME END, DEFINING IT AS A FLAVI VIRUS. THERE'S THE CORE. THERE'S THE ENVELOPE. THIS IS THE PROTEASE REGION HERE. SOME ARE ENZYMES. THIS IS AN RNA POLYMERASE. THESE ARE OTHER PROTEASES AND LINKAGE MOLECULES. IT ALSO HAS ENORMOUS DEGREE OF HETROGENEITY. THIS VIRUS IS VERY VARIABLE. PROBABLY DUE TO RAPIDITY OF REPLICATION AND ERROR-PRONE NATION AND LACK OF PROOF OF THE RNA POLYMERASE. HUMAN POLYMERASES HAVE TO BE VERY ACCURATE. THEY CAN MAKE MISTAKES. THAT'S REAL BAD. THE VIRUS DOESN'T CARE. IT'S SO FAST IT MAKES ANOTHER ONE. SO AS A RESULT, THERE'S A GREAT HETROGENEITY AND SIX GENOTYPES OF C AND THEY VARY AS MUCH AS 50%. CAN YOU IMAGINE, 50% DIFFERENCE? THAT'S A LOT. GENE TYPES OF HEPATITIS B VARY BY 10% AT MOST. THERE'S MANY, MEAN SUBTYPES OF HEPATITIS C THAT VARY BY 30%, EVEN ISLETS CAN VARY. IN THE SAME PATIENT THERE ARE DIFFERENT VIRUSES, VIRIONS, WITH DIFFERENT SEQUENCES THAT VARY UP TO 5%. SO YOU DON'T CIRCULATE A SINGLE CLONE OF VIRUS, AS YOU HAVE A QUASI SPECIES SWARM, AND IT IS THE GENOTYPES IN THE UNITED STATES. MOST IN THE UNITED STATES IS GENOTYPE 1. GENOTYPE 1A OF NORTHERN EUROPE AND THE UNITED STATES, DISCOVERED BY HOUGHTON. 1B IS WORLDWIDE. FIRST SEQUENCED BY THE JAPANESE. 2 ALSO BY THE JAPANESE. GENOTYPE 3 IS COMMON IN INDIA AND THE SUBCONTINENT. 4 IS THE AFRICAN GENOTYPE. VERY DIVERSE GENOTYPE AND WE SEE IT HERE IN AFRICAN IMMIGRANTS. YOU CANNEST IT FOR ANTIBODIES, THE U.S. FOUND 1.5% OF AMERICANS HAVE ANTIBODY TO HEPATITIS C. BUT JUST BECAUSE YOU HAVE ANTIBODY DOESN'T MEAN YOU HAVE A VIRUS, BUT WHAT'S ALSO FOUND IS 80% OF PEOPLE WITH ANTIBODY HAVE VIRUS. THIS IS THE CHRONICITY RATE OF HEPATITIS C, VERY HIGH. 70 TO 80% OF PEOPLE WITH ACUTE HEPATITIS C DEVELOP CHRONIC, AND THOSE WHO DON'T DEVELOP CHRONIC DEVELOP ANTIBODY WITHOUT VIRUS. INJECTION DRUG USE IS THE MOST COMMON RISK FACTOR. HISTORY OF TRANSUSING USED TO BE COMMON. NOW WE DON'T SEE POST-TRANSFUSION HEPATITIS C. BLOOD IS SCREENED. ONLY HALF OF PEOPLE WHO HAVE HEPATITIS C ARE AWARE THEY HAVE IT. THAT RATE IS GOING DOWN BUT IT'S STILL QUITE HIGH. IT CAN BE A SILENT DISEASE. HERE IS MY SAME PATIENT, NUMBER THREE, AND WHAT WE DID NOW IS IF THERE'S A TEST FOR HEPATITIS C WE WENT BACK AND TESTED THE STORED SPECIMENS TO FIND OUT WHAT WAS GOING. HERE IS WHAT WE DID, OF COURSE. YOU CAN IMAGINE. YOU HAVE VIRUS IN HIS BLOOD, TREATED WITH INTERFERON AND BECAME NEGATIVE. STOPPED, BECAME POSITIVE. STARTED AGAIN, BECAME NEGATIVE. THIS TIME WHEN WE STOPPED, HE REMAINED NEGATIVE FOR SIX MONTHS, AND THIS IS A YEAR-AND-A-HALF AFTER. SO IT'S A SUSTAINED LOSS OF VIRUS. AND INDEED THESE TEN PATIENTS WE TREATED, WE REEVALUATED THEM TEN YEARS LATER HERE, FIVE WERE STILL PCR NEGATIVE, AND THEY HAD NO EVIDENCE OF PERSISTENT LIVER DISEASE OR ENZYMES WERE NORMAL, THEY WERE QUITE HEALTHY. FIVE REMAINED HCV RNA POSITIVE, ALL HAVE PERSISTENT LIVER DISEASE, THREE DEVELOPED LIVER CANCER, TWO DIED. SO WHAT THIS LOOKED LIKE TO US WAS WE CURED THIS CHRONIC VIRAL INFECTION, WHICH IS SOMEWHAT UNUSUAL, ISN'T IT? LIVER BIOPSY BEFORE, AND TEN YEARS LATER THIS IS INFLAMMATION, NECROSIS, THIS IS FAIRLY NORMAL. THIS IS ANOTHER PATIENT THAT HAD FIBROSIS, A LOT OF SCARRING, ALL THIS GREEN STUFF, AND FOLLOW-UP NO FIBROSIS. LIVER HEALS ITSELF NICELY. HERE IS THIS PATIENT NOW. HE'S NOW IN HIS -- APPROACHING 60, HAS A FAMILY, HAD NORMAL ENZYMES FOR OVER 20 YEARS. NOW, IF YOU LOOK CAREFULLY YOU SEE ENZYMES ARE SLIGHTLY ON THE HIGH SIDE OF NORMAL, AREN'T THEY? I THINK MY FELLOWS WHAT KNOW WITH THAT MEANS, IN 20 YEARS HE'S GAINED A LOT OF WEIGHT AND PROBABLY HAS FATTY LIVER DISEASE NOW. LONG TERM OUTCOME, AFTER SVR, WE TOOK THE FIRST 100 PATIENTS AND GOT THEM TO COME BACK TO SEE US IN THE CLINICAL CENTER. THREE RELAPSED ACTUALLY, AND WE SHOWED IT WAS A RELAPSE, IT WASN'T REINFECTION, IT WAS THE SAME VIRUS THAT HAD COME BACK. BUT 97 WERE NEGATIVE. ONE OF THEM DEVELOPED CANCER OF THE LIVER. THAT PATIENT HAD CIRRHOSIS BEFORE WE TREATED HIM. BUT NONE HAD ACTIVE LIVER DISEASE. APPEARS TO BE A CURE. SOUNDS GOOD. THIS HAPPY GROUP IS THE SPEAKERS OF THE NIH CONSENSUS CONFERENCE WE HAD ON HEPATITIS C IN 1997, THE FIRST CONSENSUS CONFERENCE ON HEPATITIS C, AND WAS IMPORTANT FOR A COUPLE REASONS. ONE, IT BASICALLY STATED THAT YOU SHOULD TREAT HEPATITIS C. IT ACTUALLY WAS HELPFUL IN THAT REGARD, BUT IT ALSO CREATED AN AGENDA FOR THE FUTURE AND MADE SOME DEFINITIONS. ONE OF THE DEFINITIONS THAT IT CREATED WAS A SUSTAINED VIROLOGICAL RESPONSE AS END POINT, NO MORE ALT AND LIVER BIOPSY. THAT'S NOT IMPORTANT. DID THEY CLEAR THE VIRUS AND DOES IT REMAIN NEGATIVE? SOME PEOPLE RELAPSED, OTHERS HAVE A NONRESPONSE. THOSE DEFINITIONS ARE WITH US TODAY. AND THEN WHEN LARGE SCALE TRIALS WITH DONE WITH INTERFERON, IT WAS FOUND THEY WERE LACKING, RESPONSE RATES WERE POOR IN GENERAL. SO THIS IS A LARGE STUDY, DONE BY SCHERING, 231 PATIENTS TREATED WITH ALPHA INTERFERON ALONE, 27% OF PEOPLE HAD NORMAL ENZYMES AT THE END OF THE THERAPY. I'M SORRY. 27% OF PEOPLE WERE VIRUS NEGATIVE AT THE END OF THERAPY. SIX MONTHS LATER ONLY 6% WERE. A VERY LARGE RELAPSE RATE. THE OVERALL SUSTAINED RESPONSE RATE IS PRETTY POOR. WITH A YEAR OF THERAPY, THAT'S IMPROVED, BUT NOTICE YOU DON'T MAKE ANY MORE PEOPLE NEGATIVE. IF YOU'RE NOT NEGATIVE BY SIX MONTHS, YOU'RE NOT GOING TO BE NEGATIVE BY CONTINUING TREATMENT. BUT THE RELAPSE RATE IS LESS. SO THAT'S WHERE WE STOOD. INTERFERON BY ITSELF, NOT VERY GREAT RESPONSE RATES. WE NEED ANOTHER DRUG. AND WHEN MICHAEL HOUGHTON SEQUENCED HEPATITIS C VIRUS HE GAVE US A CALL AND SAID, IT'S A FLAVOVIRUS. WHAT DOES THAT MEAN? IF YOU LOOK AT THE DRUGS EFFECTIVE AGAINST THAT, THAT MIGHT LEAD YOU TO THE DRUGS THAT MIGHT BE EFFECTIVE AGAINST HEPATITIS C, SO WHAT WE DID IS WE GOT RIBAVIRIN, WHICH WAS SHOWN TO HAVE ACTIVITY AGAINST SEVERAL FLAVIVIRUSES IN CELL CULTURE, A GUANOSIN DERIVATIVE. THE SUBSTITUTION WAS NOT IN THE RIBOSE BUT IN THE NUCLEIC ACID PART, HERE. AND HAD BEEN USED, AROUND SINCE THE 197 0s. WE TRIED IT IN HEPATITIS C AND WE FOUND IT LOWERED THE LIVER ENZYMES. THIS IS A STUDY WE ENDED UP DOING, THE FINAL STUDY, A RANDOMIZED CONTROL STUDY OF RIBAVIRIN VERSUS PLACEBO FOR 12 MONTHS. A PAINFUL STUDY TOO. BECAUSE WE HAD THE LAB TESTS THAT WOULD GIVE AWAY THEIR OWN RIBAVIRIN. THE LIVER ENZYMES GO DOWN, BECOME NORMAL IN A THIRD OF PATIENTS. AND THEY GO DOWN IN VIRTUALLY EVERYONE. BUT WHEN YOU STOP, RELAPSE, PRETTY MUCH EVERYBODY RELAPSED. AND WHEN WE APPLIED HVC RNA LEVELS, NOBODY BECAME NEGATIVE. WE TREATED MORE THAN 60 PEOPLE, WITH RIBAVIRIN, NONE BECAME PCR NEGATIVE EVEN ONCE. THE LEVELS DIDN'T CHANGE. WHAT DOES RIBAVIRIN? IT DOESN'T DO VERY MUCH. IT HAD A LOT OF PROMISE BUT IN PILOT STUDIES IMPROVED ALT LEVELS BUT HAD NO EFFECT ON HCV RNA LEVELS. WHAT ABOUT THE COMBINATION OF RIBAVIRIN AND INTERFERON AND WE HAD A CLINICAL TRIAL WITH FIVE CENTERS ACROSS THE UNITED STATES, EVERYTHING SET UP, THE FDA APPROVAL, I GOT INTERFERON FROM SCHERING, THE SMALL COMPANY WAS PROVIDING THE RIBAVIRIN, READY TO GO, AND I GOT A CALL BY THE SMALL COMPANY, SAYING WE JUST SOLD RIBAVIRIN TO SCHERING, SO IT WENT OUT THE WINDOW. WE GOT TOGETHER WITH SCHERING BUT THEY WANTED TO MULTIPLY OUR TRIAL BY FOUR AND DO TWO LARGE TRIALS, ONE IN EUROPE AND ONE IN THE UNITED STATES, AND THEY WANTED TO USE THREE ARMS. INTERFERON ALONE FOR 12 MONTHS WITH RIBAVIRIN FOR THREE MONTHS AND SIX MONTHS. WE COULDN'T PARTICIPATE IN THIS. THEY HAD LIKE 50 U.S. CENTERS AND 50 EUROPEAN CENTERS. IT WAS A BIT TOO MUCH FOR US. AND THESE ARE THE FINAL RESULTS, IT SHOWED THE ADDITION OF RIBAVIRIN DOUBLED OR TRIPLED THE RESPONSE RATE. GETTING UP TO ABOUT 40%. EUROPEANS ALWAYS DO BETTER THAN THE AMERICANS WITH ALL THEIR TRIALS. THEY HAVE A HIGHER RESPONSE RATE, A LITTLE BIT HIGHER. WELL, WHAT'S THE NEXT STEP? WELL, THE NEXT STEP TURNED OUT TO BE PEBYLATION BY ADDING THIS MOLECULE TO MAKE IT A LARGER MOLECULAR WEIGHT PROTEIN, A LONGER HALF-LIFE, SO IT STAYS IN THE SERUM LONGER. YOU GET HIGHER, MORE PROLONGED LEVELS, ONCE WEEKLY INSTEAD OF THREE TIMES A WEEK INJECTIONS, A SIMILAR ADVERSE EVENT PROFILE. WAS IT MORE EFFECTIVE OR ARE WE GETTING THE SAME THING? IT TURNED OUT TO BE MORE EFFECTIVE. THESE ARE TRIALS AGAIN. NOW HERE AGAIN THIS IS THE SCHERING PRODUCT AND THIS IS THE ROCHE PRODUCT, MULTI-CENTER TRIALS, NOT U.S. VERSUS EUROPE ANYMORE. AND HERE IS WITH THE STANDARD AND PEGYLATEED. I FELT IT WAS SATISFACTORY. WE CROSSED THE 50% BARRIER, MORE THAN 50% OF PEOPLE DID RESPOND. THESE SHOWED FACTORS THAT CORRELATED, WHAT TYPE OF PATIENT RESPONDED VERSUS THOSE THAT DIDN'T? HERE IS THE MAJOR THING WHICH WAS GENOTYPE. PATIENTS WERE GENOTYPE 1, THE MOST COMMON GENOTYPE, THE RESPONSE RATE WAS AROUND 40 TO 45%. PATIENTS WITH GENOTYPES 2 AND 3, THE RESPONSE RATE WAS 75 TO 85%. NOW YOU'RE TALKING BUSINESS. NOW YOU'RE TALKING ABOUT A THERAPY. AND INDEED IN THE CLINICAL CENTER WE'VE DONE TRIALS OF INTERFERON, RIBAVIRIN, RESPONSE RATE OF 80%. THE 20%, IF YOU BRING THEM BACK AND RETREAT THEM, WE GOT 100% OF PEOPLE TO RESPOND. THAT'S IF THEY AGREED TO RETURN, NOT ALL OF THEM DID. BUT GENOTYPES 2 AND 3, THAT'S A PRETTY SATISFACTORY RESPONSE. THERE ARE OTHER THINGS THAT PREDICTED A RESPONSE AND NONRESPONSE. THIS IS ONE OF THE MORE STRIKING THINGS, AFRICAN-AMERICAN RACE. AND THIS WAS ALSO DISCOVERED AT THE CLINICAL CENTER. WHEN I LOOKED AT MY PATIENTS WHO RECOVERED AND THOSE THAT DIDN'T, I DIDN'T HAVE A SINGLE BLACK PATIENT THAT RESPONDED TO ALPHA INTERFERON ALONE. ZERO. ZERO RESPONSE RATE. AND EVEN WITH RIBAVIRIN AND INTERFERON AND PEGYLATED INTERFERON, THIS IS THE BEST WE CAN DO, THIS IS AN EXTRAMURAL TRIAL WE CONDUCTED. 200 CAUCASIAN AMERICANS VERSES 200 AFRICAN-AMERICANS, SAME DOSE, SAME THERAPY, RESPONSE RATE 5 2% VERSUS 28, ABOUT HALF. WE LOOKED AT COMPLIANCE AND EVERYTHING ELSE. THERE WAS NOTHING BUT RACIAL DIFFERENCE AND RESPONSE RATE. SO WHAT IS THAT? RACIAL DIFFERENCES SHOULD IMMEDIATELY ALERT YOUR MIND THERE'S PROBABLY A GENETIC DIFFERENCE AND INDEED THERE WAS. THIS IS A GWA STUDY DONE ON A GROUP OF PATIENTS WHO RESPONDED OR DIDN'T RESPOND, COMPARING THE TWO, THERE WAS A VERY STRONG HIT, VERY CONVINCING, 10 TO THE MINUS 50 OR SOMETHING LIKE THAT. IT TURNED OUT TO BE A GENE CALLED -- CLOSE TO A GENE CALLED IL-28B, EVERYBODY SCRATCHED THEIR HEAD AND TRIED TO FIND WHAT IL-28 WAS. IT'S A LAMBDA INTERFERON. IT'S A VERY INTERESTING ISSUE, PURSUED A LOT. THIS IS A MAP OF THE WORLD, AND THE BLUE IS THE RESISTANT GENE AND GREEN IS THE SENSITIVE GENE. VERY INTERESTING. THE WILD-TYPE GENE IS AFRICAN. THAT'S THE NORMAL GENE. THE IL-28B ASSOCIATED WITH RESPONSE TO INTERFERON IS A DEFECTIVE GENE. INTERESTING. BUT IT OBVIOUSLY IS SELECTED FOR BECAUSE IN ASIA, IT'S VERY COMMON. AND IN EUROPE, MUCH MORE COMMON THAN IN AFRICA. RESPONSE RATE, SO THAT'S AN INTERESTING ISSUE. MIGHT HAVE REMAINED IMPORTANT BUT THINGS COME OUT. HERE IS THE FIRST TEN YEARS OF INTERFERON WAS LICENSED FIRST FOR HEPATITIS C IN 1991, BY 2002 WHAT AN AMAZING PROGRESS WE WOULD BE MAKING. THE PROBLEM IS WITH THE NEXT TEN YEARS WE DIDN'T GET ANYWHERE. WE TRIED HIGHER DOSES OF INTERFERON, DIFFERENT COURSES OF INTERFERON, TRIED HIGHER DOSES OF RIBAVIRIN, GIVEN IN DIFFERENT WAYS. NOTHING. COULD NOT IMPROVE THIS RESPONSE RATE. WITH HIGHER DOSES OF INTERFERON I COULD MAKE MORE PEOPLE NEGATIVE, BUT THEY WOULD RELAPSE. SO WE'RE REALLY AT -- OBVIOUSLY WE NEED ANOTHER DRUG, AND THEN WE GO BACK TO THE STRUCTURE OF THE HEPATITIS C VIRUS, PARTICULARLY THE NONSTRUCTURAL REGIONS FOR TARGETS FOR ANTIVIRAL THERAPY, DIRECT ANTIVIRAL THERAPIES, THE FIRST WERE THE PROTEASE INHIBITORS, CAN BE THAT MADE PROTEASE INHIBITORS FOR HIV MOVED INTO HEPATITIS C, A COUPLE CAME OUT. THE FIRST TWO IN 19 -- IN 2011. WHAT THESE TRIALS ARE IS THEY CARED PEG ALONE FOR 12 MONTHS AND THE PROTEASE INHIBITORS, IT'S AN ADD-ON THEY WERE. YOU CAN SEE THE RESPONSE RATE GOES FROM 40 TO 45% UP TO 70%. THERE'S A MORE MODERN SOMEWHAT BETTER TOLERATED POLYMERASE, AND THE RESPONSE RATE IS GREATER. THIS IS GREAT PROGRESS. THE PROBLEM IS YOU'RE STILL GIVING PEOPLE A YEAR OF INTERFERON AND THAT'S DIFFICULT. FOR INSTANCE, THESE TWO REGIMENS, THE FRENCH DID A TRIAL IN CIRRHOSIS PATIENTS AND THE MORTALITY RATE WAS 3% ON THERAPY. AND THAT GOES TO THE PROBLEM WITH ALL THE TREATMENTINGS UP TO NOW IS THE RESPONSE RATES OF 70 TO 80% COULD BE ACHIEVED BUT TOLLERRABLEITY REMAINED THE LIMITING FACTOR, ONLY HALF DON'T HAVE CONTRADICTIONS. THE OTHER HALF HAVE INJECTION DRUG USE OR SEVERE DIABETES OR HEART OR LUNG DISEASE OR IMMUNOSUPPRESSION OR LIVER TRANSPLANT. A LOT OF PEOPLE DON'T WANT TO BOTHER. IN COMMUNITY PRACTICE IN THE SO-CALLED REAL WORLD, LOOK AT ALL PATIENTS IN HEPATITIS C, ONLY 10 TO 15% WERE GOING TO BE CURED, COULD BE TREATED AND WOULD RESPOND. WITH THAT TYPE OF RATE, YOU'RE NOT GOING TO MAKE MUCH OF A DENT IN THIS DISEASE, AND WE OBVIOUSLY NEED INTERFERON PRE-REGIMENS, PRE--- INTERFERON-FREE REGIMENS. THIS REGION IS RNA POLYMERASE, SO YOU THINK YOU COULD DEVELOP RNA POLYMERASE INHIBITORS. THIS IS AN INTERESTING REGION, NONSTRUCTURAL 5A, IT'S NOT AN ENZYME, IT'S A POLYPEPTIDE SEQUENCE THAT APPEARS TO TETHER THE POLYMERASE TO THE ENDOPLASMIC RETICULUM. THE REPLICATED COMPLEX IS NOT CREATED AND POLYMERASE DRIFTS AWAY INTO THE CYTOPLASM. THAT'S MY SIMPLISTIC EXPLANATION OF NS 5A, THEY DEVELOPED INVECTORS OF IT THAT PREVENT -- THAT INHIBIT BUT THEY PREVENT IT EMBEDDING INTO THE ER. THIS IS A COMPLETELY NEW CONCEPT IN ANTIVIRAL THERAPY, BY THE WAY. IT WAS DISCOVERED BY HIGHER THROUGH-PUT SCREENING USING ONE OF THESE STRUCTURES. RNA POLYMERASE INHIBITORS CAME ALONG AND THIS IS THE MOST IMPORTANT ONE, SOFOSBUVIR. HERE IS THE RIBOSE MOLECULE, A SUBSTITUTION OF FLUERINE. IN ADDITION IT HAS A PHOSPATE GROUP. FOR NUCLEOSIDE ANALOGS TO WORK THEY HAVE TO BECOME TRIPHOSPHATES, IN THE CELL AND THEN THAT'S WHAT BLOCKS THE RNA POLYMERASE, IT INHIBITS, IT COMPETES WITH THE REGULAR TRIPHOSPHATES. SO WHY WAS THIS STRUCTURE IMPORTANT? WELL, THIS MOLECULE INHIBITS HEPATITIS C VIRUS IF YOU INJECT IT, ADD IT TO CELLS. THE TROUBLE WITH THIS MOLECULE IS THAT IT'S VERY POORLY PHOSPHORYLATED. IT DOESN'T BECOME THE TRIPHOSPHATE. WE HAD THE FIRST PHOSPATE ON IT, IT WILL BE TRIPHOSPHORYLATED. TROUBLE IS THIS IS USUALLY DIGESTED OFF, IN THE STOMACH OR IN OTHER TISSUES IN THE BLOOD. SO YOU CAN'T GET IT IN. SO WHAT THIS MOLECULE HAS IS THIS CLUMSY LOOKING THING, THE McQUIGEN THAT PROTECTS THE PHOSPATE GROUP SO IT'S NOT DIGESTED OFF. IT TAKES OFF THIS CAP. RELEASE IT INTO THE CELL. BEAUTIFUL. VERY ELEGANT. YOU KNOW, HAVE YOU TO BE CAREFUL WHEN YOU INHIBIT RNA POLYMERASE, IF YOU INHIBIT HUMAN POLYMERASE YOU DON'T MAKE PROTEIN AND RAPIDLY GET IN TROUBLE. THIS IS SPECIFIC TO THE VIRUS. AND HERE IS THE NEXT MOLECULE, THE LEDISPASIVIR. I DON'T KNOW WHAT IT LOOKS LIKE. I KEEP ASKING PEOPLE, WHAT IS THIS MOLECULE? IS IT A PROTEIN MEMETIC DRUG OR WHAT? THEY WERE FOUND BY THROUGH-PUT -- HIGH THROUGH-PUT SCREENING. IT IT'S VERY EFFECTIVE AGAINST HEPATITIS C VIRUS. TWO WEEKS AGO THE FDA APPROVED THIS COMBINATION FOR HEPATITIS C GENOTYPE 1. AND HERE ARE THE TRIALS THAT SHOWED ITS EFFECT. LOOK AT THAT. 99%. THAT'S PRETTY GOOD, RIGHT? YOU CAN NEVER GET 100%. YOU LOSE SOMEONE. THIS IS WITH 12 WEEKS OF TREATMENT, NOT A YEAR, NOT SIX MONTHS. 12 WEEKS. THEY LOOKED AT 12 VERSUS 24 WEEKS, OBVIOUSLY NOT IMPORTANT. PEOPLE NOT TREATED, PEOPLE PREVIOUSLY TREATED, BUT 98% IS FANTASTIC. HERE IS THE ANALYSIS OF THAT PREVIOUSLY TREATED GROUP AND OVERALL RESPONSE RATE WAS A LITTLE BIT LOW WITH THE SHORTER COURSE OF THERAPY, THEY SHOW THE CIRHOTTIC PATIENTS NEED THE 24 WEEKS. IT'S BON APPROVED FOR USE AT 12 WEEKS, PREVIOUSLY TREATED PATIENTS MAY NEED 24. VERY NEAT. THEY HAVE ALSO FORMULATED, FORMULATED THI S AS A SINGLE TABLET, ONE PILL A DAY, NO INJECTION. THEY ALSO STUDIED IT FOR EIGHT WEEKS VERSUS 12 WEEKS TO SEE IF THEY CAN COULD GET AWAY WITH A SHORTER COURSE, IT WASN'T TOO DIFFERENT BUT IF YOU LOOKED AT WHAT PREDICTED NOT RESPONDING, IT WAS HIGH LEVELS OF VIRUS TO BEGIN WITH, SO THE PATIENTS WITH HIGH LEVELS OF VIRUS, THEY ONLY HAD A RESPONSE RATE OF 90%, WITH EIGHT WEEKS OF TREATMENT. ONLY 90. AMAZING WHAT WE'RE DISSATISFIED WITH NOW. WE WANT 98%. SO A PREVIOUSLY UP TREATED PATIENT, TREATMENT NAIVE PATIENTS, WITH LOW OR MODERATE LEVELS OF VIRUS CAN BE TREATED, THAT WAS APPROVED ABOUT TWO WEEKS AGO. WELL, THIS COMBINATION HAS NOT BEEN APPROVED YET BUT RESULTS HAVE BEEN PUBLISHED. AND THIS COMBINATION OF ORAL AGENTS WOULD PROBABLY BE APPROVED IN THE NEXT SIX OR MONTHS, I DON'T KNOW FOR SURE, BUT THE RESPONSE RATES ARE SIMILAR. TREATMENT NAIVE PATIENTS, 12 WEEKS, THIS IS ACTUALLY NOT TWO DRUGS BUT ACTUALLY FOUR DRUGS FOR HEPATITIS C, INCLUDING RIBAVIRIN. INTERESTING, THAT MOLECULE STAYS WITH US. 12 WEEKS, 96%, EVEN IN PREVIOUSLY TREATED PATIENTS, QUITE REMARKABLE. SO WHAT DO WE HAVE HERE? WE THAT THE PROGRESS OF THERAPY, HEPATITIS C. WE HAD THAT PERIOD HERE WHERE IT WAS A BIT SLOW, BUT NOW I THINK WE'RE AT THE END OF THE STORY, END OF MY SLIDE. IT GOES OFF THE TOP. SO THE BARRIERS TO TREATMENT WHICH WERE DIFFICULTY OF TAKING INTERFERON, THE SIDE EFFECTS, THE LACK OF RESPONSE IN SOME PATIENTS, HAVE ALL BEEN LIFTED. THIS IS EIGHT OR TWELVE WEEKS OF ONE PILL A DAY, MAYBE TWO. WELL, ALMOST ALL THE BARRIERS HAVE BEEN LIFTED. THERE REMAINS ONE BARRIER, AND IT'S THE SERIOUS BARRIER. RESPONSE RATES OF 95 TO 99%, 12 WEEKS, MINIMAL SIDE EFFECTS. REALLY PROMISES TO MAKE A REAL IMPACT ON THE MORBIDITY AND MORTALITY OF THIS DISEASE, SO THIS CAN BE CURED. BUT THE REMAINING BARRIERS IS COST. THIS COMBINATION FOR 12 WEEKS HAS BEEN PRICED AT $96,000. THAT'S FOR 12 WEEKS. THAT'S ONE PILL A DAY, THAT'S ABOUT $1250 PER PILL. YOU DON'T WANT TO DROP THEM DOWN THE TOILET. TO TREAT, IT'S ESTIMATED TO TREAT HEPATITIS C IN AMERICA, AND REMEMBER WE DON'T KNOW ALL AMERICANS WHO HAVE THIS DISEASE, IT'S ESTIMATED IN THE NEXT FEW YEARS WILL COST $100 BILLION. AND REMEMBER, THAT THIS IS THE DISEASE THAT OFTEN OCCURS IN DISADVANTAGED PEOPLE, ONLY -- IT'S ESTIMATED ONLY 25% OF PEOPLE IN THE UNITED STATES WITH HEPATITIS C HAVE INSURANCE. THE REST IS PUBLIC, I.E. YOU AND ME, WE'LL BE PAYING FOR IT. IT'S A ENORMOUS BURDEN TO AN ALREADY BURDENED MEDICAL CARE SYSTEM, I CALL IT THE UNAFFORDABLE CARE ACT. I DON'T KNOW WHAT'S GOING TO HAPPEN. HERE IS MY FINAL SLIDE TO SHOW YOU THE COST OF SUCCESS. WHEN INTERFERON FOR SIX MONTHS WAS LICENSED, IT WAS $2500. THAT WAS PRETTY EXPENSIVE, I THOUGHT. FOR 12 MONTHS, IT WAS 5K. NOW, THEY'D ADDED RIBAVIRIN, IT SHOULD BE -- I MEAN 5K PLUS RIBAVIRIN, THEY WERE CHARGING AN ENORMOUS AMOUNT. I WROTE A BUNCH OF NASTY LETTERS TO SCHERING. THEY HAD HUMOROUS REPLIES AND THOUGHT IT WAS FUNNY. I FIND THAT INTERESTING. WELL, IF PEGYLATED INTERFERON BECAME MORE EXPENSIVE, AT THIS TIME RIBAVIRIN BECAME GENERIC, SO WHEN THEY ADD A PROTEASE INHIBITOR, YOU ADD ON $33,000, WHICH IS ALMOST $50,000, BECOMING QUITE PRICY, WASN'T IT? AND NOW WITH THE DIRECT AGENTS, VERY GOOD RESPONSE RATE, BUT ALMOST $100,000. AND THIS IS FOR THREE MONTHS. YOU SEE, THESE WERE FOR 12 MONTHS. YOU COULD ARGUE THERE. SO I THINK WE DO FACE A PROBLEM IN HEPATITIS C, BUT THE SATISFACTION IS THAT AFTER 30 YEARS, STARTED IN THIS BUILDING A COUPLE FLOORS UP FROM HERE, THERE IS NOW THERAPY FOR VIRTUALLY EVERYONE WITH THIS DISEASE. SO THE PAST AND THE PRESENT, THIS IS THE PAST. THESE ARE THE MANY FELLOWS THAT PASSED THROUGH MY LAB OVER THE YEARS, THEY REALLY DID ALL THE WORK AND TOOK CARE OF ALL THESE PATIENTS GIVING THEM INTERFERON, FROM THE VERY BEGINNING TO THE CURRENT ONES. I'VE PUT IN YELLOW THE ONES THAT ARE STILL HERE IN THE CLINICAL CENTER, NOT ALL OF THEM WORK IN THE LIVER UNIT BUT MANY OF THEM DO. AND IT'S REALLY -- THEY HAVE DONE THE WORK THAT I'M SHOWING YOU HERE. THIS IS THE FUTURE OF THE LIVER DISEASES BRANCH A FEW WEEKS AGO. YOU CAN SEE WE'RE A HAPPY BUNCH, WE'RE ALL SMILING BECAUSE WE KNOW THERE'S MANY CHALLENGES AHEAD AND WE THINK WE CAN TAKE THEM ON. THANK YOU VERY MUCH. [APPLAUSE] >> WELL, THANK YOU, JAY, FOR A LECTURE THAT CERTAINLY TYPIFIES WHAT THIS LECTURE SERIES IS ALL ABOUT. WE HAVE TIME FOR A FEW QUESTIONS, AND IF YOU WOULD PLEASE USE THE MICROPHONES IN THE AISLE, AND AFTER THE QUESTIONS WE WILL ADJOURN TO A MORE INFORMAL SETTING ACROSS THE HALL IN THE LIBRARY FOR SOME REFRESHMENTS AND CASUAL DISCUSSION. QUESTION HERE ON THE RIGHT PLEASE. >> YES, MANY YEARS AGO I SAW AN INCIDENTALLAL FINDING, AN AUTOPSY OF TWO ORIENTAL YOUNG LADIES INVOLVED IN A TRAFFIC ACCIDENT, THEY WERE HIT BY A TRAIN, LIVERS HAD WHAT LOOKED TO ME LIKE A DIFFUSE NODULAR HYPERPLASIA OF THE LIVER COMPRESSING ALL STRUCTURES INCLUDING THE TRIAD, PORTAL VEIN, ET CETERA. I WAS THINKING COULD THIS BE A COMPLICATION OF HEPATITIS? THIS WAS AFTER 1990 SO HEPATITIS C OR SOMETHING, I REPORTED AS A DIFFUSE NODULAR HYPERPLASIA IN THE REPORT. SUBSEQUENT TO THAT I WAS THINKING ABOUT IT, A FEW DAYS BACK, I WENT THROUGH THE LITERATURE AND FOUND OUT IN CHINA, THIS IS NOW A VERY WELL DEFINED ENTITY IN TERMS OF DIFFUSE NODULAR HYPERPLASIA OF THE LIVER WITH COMPRESSION OF THE PORTAL VEIN, AND PORTAL HYPERTENSION, ET CETERA. DOES THIS HAVE ANY RELATIONSHIP TO HEPATITIS C IN YOUR EXPERIENCE AND DOES IT I HAVE ANY RELEVANCE TO TREATMENT OF HEPATITIS C? >> OKAY, SO I'M GOING TO REINTERPRET THAT QUESTION FOR DR. HOOFNAGLE. DIFFUSE NODULAR HYPERPLASIA OF THE LIVER NOW SEEN IN CHINA AS A RATHER COMMON EVENT HAVE ANY RELATIONSHIP HEPATITIS C, DO WE KNOW? >> NODULAR REGENERATIVE HYPERPLASIA, IS IN A WHAT YOU MEAN? >> OR FOCAL NODULAR HYPERPLASIA. >> FOCAL NODULAR HYPERPLASIA IS SOMETHING DIFFERENT, SEEN HERE IN FEMALES WHO TAKE ESTROGEN I THINK. I'M TALKING ABOUT A STRANGER PHENOMENA IN THE CHINESE LITERATURE, IT IS A DIFFUSE NODULAR HYPERPLASIA OF THE LIVER, ALL OVER THE PLACE. >> WELL, NODULAR REGENERATIVE HYPERPLASIA IS A FASCINATING SYNDROME BEING STUDIED BY THE LIVER UNIT, OCCURS IN MANY DISEASES. JOHN GALLIN KNOWS WELL, AND TYPICALLY IN PATIENTS WHO HAVE A CHRONIC ILLNESS AND RECEIVE MULTIPLE MEDICATIONS AND HAVE MANY COMPLICATED THINGS LIKE GRANULOMA DISEASE OF CHILDREN, AND SICKLE CELL ANEMIA, CYSTIC FIBROSIS, AND THEY GET -- IT LOOKS LIKE CIRRHOSIS BUT THERE'S NO FIBROSIS AND APPEARS TO BE A RESULT TO INJURY TO SMALL VESSELS OF THE LIVER, IT DOESN'T SEEM TO BE RELATED TO HEPATITIS C. HEPATITIS C CREATES A FULL FLOWN CIRRHOSIS. >> THANK YOU. >> WHY DON'T WE ADJOURN ACROSS THE HALL FOR REFRESHMENTS AND AGAIN CONGRATULATE DR. HOOFNAGLE. [APPLAUSE] [END OF PROGRAM]