1 00:00:09,051 --> 00:00:11,253 WELCOME TO THE CLINICAL CENTER GRAND ROUNDS, 2 00:00:11,253 --> 00:00:15,057 A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND 3 00:00:15,057 --> 00:00:17,693 HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL 4 00:00:17,693 --> 00:00:20,662 CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN 5 00:00:20,662 --> 00:00:22,464 BETHESDA, MD. 6 00:00:22,464 --> 00:00:26,001 THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY 7 00:00:26,001 --> 00:00:29,705 DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL 8 00:00:29,705 --> 00:00:32,641 EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING 9 00:00:32,641 --> 00:00:34,810 TOMORROW'S CURES. 10 00:00:34,810 --> 00:00:43,957 LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV 11 00:00:43,957 --> 00:00:46,259 GOOD AFTERNOON AND WELCOME TO 12 00:00:46,259 --> 00:00:47,794 THE CLINICAL CENTER GRAND 13 00:00:47,794 --> 00:00:48,762 ROUNDS. 14 00:00:48,762 --> 00:00:52,966 THE HOPKINS CME ACTIVITY CODE IS 15 00:00:52,966 --> 00:00:53,466 57906. 16 00:00:53,466 --> 00:00:55,268 PLEASE TEXT THIS CODE TO JOHNS 17 00:00:55,268 --> 00:00:57,036 HOPKINS CME PHONE NUMBER SHOWN 18 00:00:57,036 --> 00:00:58,438 ON THE SLIDE TO RECEIVE CREDIT 19 00:00:58,438 --> 00:00:59,372 FOR THIS LECTURE. 20 00:00:59,372 --> 00:01:02,342 WE KINDLY INVITE YOU TO PROVIDE 21 00:01:02,342 --> 00:01:03,977 FEEDBACK BY SCANNING THE QR CODE 22 00:01:03,977 --> 00:01:04,611 SHOWN ON THE SLIDE. 23 00:01:04,611 --> 00:01:06,579 FOR THOSE APPLYING FOR CMEs, 24 00:01:06,579 --> 00:01:08,481 YOU'LL RECEIVE A SURVEY LINK VIA 25 00:01:08,481 --> 00:01:09,649 EMAIL AND THIS SURVEY WILL BE 26 00:01:09,649 --> 00:01:10,417 USED TO PROVIDE US WITH 27 00:01:10,417 --> 00:01:11,818 IMPORTANT FEEDBACK ABOUT THIS 28 00:01:11,818 --> 00:01:13,486 PRESENTATION AND ALLOW YOU TO 29 00:01:13,486 --> 00:01:16,456 SUBMIT SUGGESTIONS FOR FUTURE 30 00:01:16,456 --> 00:01:17,657 GRAND ROUNDS TOPICS. 31 00:01:17,657 --> 00:01:18,725 FOLLOWING THE PRESENTATION 32 00:01:18,725 --> 00:01:20,260 QUESTIONS FOR THE SPEAKERS WILL 33 00:01:20,260 --> 00:01:21,394 BE TAKEN FROM THE MICROPHONES IN 34 00:01:21,394 --> 00:01:23,229 THE AISLES. 35 00:01:23,229 --> 00:01:24,631 ADDITIONAL LIVID YOE CAST 36 00:01:24,631 --> 00:01:26,166 VIEWERS CAN SUBMIT QUESTIONS BY 37 00:01:26,166 --> 00:01:27,267 SCROLLING DOWN AND CLICKING THE 38 00:01:27,267 --> 00:01:28,802 LIVE FEEDBACK BUTTON LOCATED ON 39 00:01:28,802 --> 00:01:30,770 THE VIDEOCAST WEBSITE. 40 00:01:30,770 --> 00:01:32,071 QUESTIONS WILL BE ANSWERED IF 41 00:01:32,071 --> 00:01:33,373 TIME PERMITS AT THE CONCLUSION 42 00:01:33,373 --> 00:01:34,908 OF THE PRESENTATION. 43 00:01:34,908 --> 00:01:45,084 TODAY WE ARE HONORED TO HAVE DRM 44 00:01:45,084 --> 00:01:52,992 KOTTILIL. 45 00:01:52,992 --> 00:01:54,494 DR. HELLER EARNED HIS 46 00:01:54,494 --> 00:01:57,230 MEDICAL DEGREE AT THE UNIVERSITY 47 00:01:57,230 --> 00:02:01,401 OF WITTER -- SOUTH AFRICA, AND 48 00:02:01,401 --> 00:02:03,036 COMPLETED HIS RESIDENCY TRAINING 49 00:02:03,036 --> 00:02:04,404 IN INTERNAL MEDICINE AT 50 00:02:04,404 --> 00:02:05,572 GEORGETOWN UNIVERSITY. 51 00:02:05,572 --> 00:02:07,307 FOLLOWED BY A POSTDOCTORAL 52 00:02:07,307 --> 00:02:08,341 FELLOWSHIP AT THE NATIONAL 53 00:02:08,341 --> 00:02:10,176 INSTITUTE OF ALLERGY AND 54 00:02:10,176 --> 00:02:12,212 INFECTIOUS DISEASES. 55 00:02:12,212 --> 00:02:13,213 DR. HELLER THEN COMPLETED 56 00:02:13,213 --> 00:02:16,583 FELLOWSHIP TRAINING IN 57 00:02:16,583 --> 00:02:17,884 GASTROENTEROLOGY AND HEPATOLOGY 58 00:02:17,884 --> 00:02:19,552 FELLOWSHIP AT NIDDK, AFTER WHICH 59 00:02:19,552 --> 00:02:22,722 HE JOINED AS STAFF. 60 00:02:22,722 --> 00:02:23,590 DR. HELLER'S SCIENTIFIC 61 00:02:23,590 --> 00:02:26,326 INTERESTS ENCOMPASS CLINICAL 62 00:02:26,326 --> 00:02:30,129 AND -- WORK INCLUDING HEPATITIS 63 00:02:30,129 --> 00:02:32,365 D, RARE LIVER DISEASES AND THE 64 00:02:32,365 --> 00:02:33,566 GUT LIVER AXIS. 65 00:02:33,566 --> 00:02:35,835 HE HAS AUTHORED OR CO-AUTHORED 66 00:02:35,835 --> 00:02:37,403 OVER 250 PAPERS AND BOOK 67 00:02:37,403 --> 00:02:37,670 CHAPTERS. 68 00:02:37,670 --> 00:02:38,905 IN ADDITION TO CONTRIBUTING 69 00:02:38,905 --> 00:02:40,106 CLINICAL MANAGEMENT GUIDELINES 70 00:02:40,106 --> 00:02:43,109 FOR THE MANAGEMENT OF CHRONIC 71 00:02:43,109 --> 00:02:45,245 HEPATITIS C, DEMANDS OF 72 00:02:45,245 --> 00:02:46,779 HEALTHCARE WORKERS LIVING WITH 73 00:02:46,779 --> 00:02:48,081 VIRAL HEPATITIS, AND 74 00:02:48,081 --> 00:02:50,316 ESTABLISHING CRITERIA FOR 75 00:02:50,316 --> 00:02:52,585 CLINICAL TRIALS IN CHRONIC GRAFT 76 00:02:52,585 --> 00:02:54,020 VERSUS HOST DISEASE. 77 00:02:54,020 --> 00:02:55,421 DR. HELLER HAS SERVED AS 78 00:02:55,421 --> 00:02:59,626 EDITORIAL BOARD MEMBER FOR THE 79 00:02:59,626 --> 00:03:01,127 JOURNALS GASTROENTEROLOGY AND 80 00:03:01,127 --> 00:03:01,561 HEPATOLOGY. 81 00:03:01,561 --> 00:03:02,862 HE'S RECEIVED NUMEROUS AWARDS 82 00:03:02,862 --> 00:03:06,266 FOR HIS WORK AS EDUCATOR AND 83 00:03:06,266 --> 00:03:07,267 MENTOR FROM GEORGETOWN 84 00:03:07,267 --> 00:03:09,202 UNIVERSITY HOSPITAL, THE FACULTY 85 00:03:09,202 --> 00:03:10,169 TEACHER AWARD FROM THE DIVISION 86 00:03:10,169 --> 00:03:13,339 OF MEDICINE, DIVISION OF 87 00:03:13,339 --> 00:03:14,240 GASTROENTEROLOGY AND HEPATOLOGY 88 00:03:14,240 --> 00:03:17,176 AT MARYLAND AND IS TWICE 89 00:03:17,176 --> 00:03:19,712 RECIPIENT OF NIDDK'S MENTORSHIP 90 00:03:19,712 --> 00:03:20,813 AWARD AS WELL AS YOU MAKE A 91 00:03:20,813 --> 00:03:21,381 DIFFERENCE AWARD. 92 00:03:21,381 --> 00:03:23,416 HIS CLINICAL RESEARCH HAS BEEN 93 00:03:23,416 --> 00:03:25,151 RECOGNIZED WITH AN NIDDK EARLY 94 00:03:25,151 --> 00:03:29,222 CAREER INVESTIGATOR AWARD, NIAID 95 00:03:29,222 --> 00:03:33,826 MERIT AWARD AND NIDDK INNOVATION 96 00:03:33,826 --> 00:03:35,461 AWARD. 97 00:03:35,461 --> 00:03:36,329 NATIONAL CANCER INSTITUTE 98 00:03:36,329 --> 00:03:37,163 DIRECTOR'S AWARD FOR CLINICAL 99 00:03:37,163 --> 00:03:37,430 SCIENCE. 100 00:03:37,430 --> 00:03:39,165 AND THIS PAST APRIL, DR. HELLER 101 00:03:39,165 --> 00:03:41,234 WAS HONORED TO PRESENT A 102 00:03:41,234 --> 00:03:43,002 CLINICAL CENTER GRAND ROUNDS 103 00:03:43,002 --> 00:03:44,003 DISTINGUISHED CLINICAL RESEARCH 104 00:03:44,003 --> 00:03:48,908 SCHOLAR AND EDUCATOR LECTURE. 105 00:03:48,908 --> 00:03:49,976 DR. KOTTILIL IS INTERIM DIRECTOR 106 00:03:49,976 --> 00:03:51,844 OF THE INSTITUTE OF HUMAN 107 00:03:51,844 --> 00:03:53,613 VIROLOGY AT THE UNIVERSITY OF 108 00:03:53,613 --> 00:03:54,180 MARYLAND SCHOOL OF MEDICINE 109 00:03:54,180 --> 00:03:56,449 WHERE HE'S PROFESSOR OF 110 00:03:56,449 --> 00:03:57,650 MEDICINE, CHIEF OF THE DIVISION 111 00:03:57,650 --> 00:03:58,785 OF INFECTIOUS DISEASES AND 112 00:03:58,785 --> 00:04:00,820 SCIENTIFIC DIRECTOR OF THE NIH 113 00:04:00,820 --> 00:04:01,688 DISTRICT OF COLUMBIA PARTNERSHIP 114 00:04:01,688 --> 00:04:03,990 FOR AIDS PROGRESS. 115 00:04:03,990 --> 00:04:05,558 DR. KOTTILIL EARNED HIS 116 00:04:05,558 --> 00:04:06,826 MEDICAL DEGREE AT GOVERNMENT 117 00:04:06,826 --> 00:04:11,197 MEDICAL COLLEGE IN INDIA, AND 118 00:04:11,197 --> 00:04:13,166 HIS PH.D. FROM CANADA. 119 00:04:13,166 --> 00:04:15,802 HE COMPLETED HIS RESIDENCY IN 120 00:04:15,802 --> 00:04:18,771 INTERNAL RES DEN SEAL AT BROWN 121 00:04:18,771 --> 00:04:20,740 UNIVERSITY AND WAS STAFF 122 00:04:20,740 --> 00:04:24,410 CLINICIAN AT NIAID FROM 2003 TO 123 00:04:24,410 --> 00:04:24,677 2014. 124 00:04:24,677 --> 00:04:26,346 WHERE HE WAS RECIPIENT OF 125 00:04:26,346 --> 00:04:27,647 NUMEROUS BENCH TO BEDSIDE AWARDS 126 00:04:27,647 --> 00:04:29,916 AND OTHERS. 127 00:04:29,916 --> 00:04:30,950 DR. KOTTILIL'S RESEARCH 128 00:04:30,950 --> 00:04:31,784 INTERESTS INCLUDE THE 129 00:04:31,784 --> 00:04:33,853 PATHOGENESIS OF CHRONIC VIRAL 130 00:04:33,853 --> 00:04:35,288 INFECTIONS AND RESEARCH TO 131 00:04:35,288 --> 00:04:36,489 ERADICATE CHRONIC PERSISTENT 132 00:04:36,489 --> 00:04:37,357 VIRAL INFECTIONS BY TARGETING 133 00:04:37,357 --> 00:04:39,359 THE VIRUS AND THE HOST. 134 00:04:39,359 --> 00:04:41,194 HE HAS CONDUCTED SEVERAL 135 00:04:41,194 --> 00:04:43,596 INVESTIGATOR INITIATED STUDIES 136 00:04:43,596 --> 00:04:45,164 IN HEPATITIS C AND HAS SERVED AS 137 00:04:45,164 --> 00:04:47,634 ONE OF THE FOUNDING MEMBERS OF 138 00:04:47,634 --> 00:04:48,735 NATIONAL HEPATITIS C TREATMENT 139 00:04:48,735 --> 00:04:49,602 GUIDANCE PANEL. 140 00:04:49,602 --> 00:04:52,105 A PROLIFIC INVESTIGATOR AND 141 00:04:52,105 --> 00:04:53,640 NATIONALLY RECOGNIZED SPEAKER, 142 00:04:53,640 --> 00:04:55,608 DR. KOTTILIL HAS OVER 300 143 00:04:55,608 --> 00:04:56,376 PEER-REVIEWED PUBLICATIONS AND 144 00:04:56,376 --> 00:05:01,514 BOOK CHAPTERS AND CONTINUES TO 145 00:05:01,514 --> 00:05:04,851 DO WORK SUPPORTED BY NUMEROUS 146 00:05:04,851 --> 00:05:05,952 NIH GRANTS. 147 00:05:05,952 --> 00:05:07,754 HE'S RECIPIENT OF THE HIDNA AND 148 00:05:07,754 --> 00:05:09,689 RICHARD ROSENTHAL AWARD FROM THE 149 00:05:09,689 --> 00:05:10,957 AMERICAN COLLEGE OF PHYSICIANS. 150 00:05:10,957 --> 00:05:13,059 HE HAS AN ELECTED MEMBER OF THE 151 00:05:13,059 --> 00:05:14,994 INFECTIOUS DISEASES SOCIETY OF 152 00:05:14,994 --> 00:05:16,062 AMERICA, AND AMERICAN SOCIETY OF 153 00:05:16,062 --> 00:05:17,597 LIVER DISEASES, AND THE AMERICAN 154 00:05:17,597 --> 00:05:19,499 COLLEGE OF PHYSICIANS. 155 00:05:19,499 --> 00:05:20,867 HE HAS BEEN AWARDED DESIGNATION 156 00:05:20,867 --> 00:05:22,468 OF MASTER BY THE AMERICAN 157 00:05:22,468 --> 00:05:25,038 COLLEGE OF PHYSICIANS. 158 00:05:25,038 --> 00:05:26,572 THE TITLE OF THEIR PRESENTATION 159 00:05:26,572 --> 00:05:28,875 TODAY IS HEPATITIS D AND 160 00:05:28,875 --> 00:05:30,109 POTENTIAL TARGETS FOR TREATMENT. 161 00:05:30,109 --> 00:05:31,711 SO NOW PLEASE JOIN ME IN 162 00:05:31,711 --> 00:05:33,012 WELCOMING OUR SPEAKERS, 163 00:05:33,012 --> 00:05:34,480 DR. HELLER AND DR. KOTTILIL. 164 00:05:34,480 --> 00:05:42,555 [APPLAUSE] 165 00:05:42,555 --> 00:05:44,724 >> THANK YOU FOR THAT VERY KIND 166 00:05:44,724 --> 00:05:45,058 INVITATION. 167 00:05:45,058 --> 00:05:46,592 THANK YOU ALL FOR BEING HERE. 168 00:05:46,592 --> 00:05:47,827 IT'S ESPECIALLY EXCITING FOR ME 169 00:05:47,827 --> 00:05:50,863 TO PRESENT WITH DR. KOTTILIL. 170 00:05:50,863 --> 00:05:54,500 WE'RE OLD FRIENDS, AND HE NEVER 171 00:05:54,500 --> 00:05:56,869 CEASES TO, AS YOU'LL SEE, 172 00:05:56,869 --> 00:05:58,304 IMPRESS WITH HIS INNATE 173 00:05:58,304 --> 00:06:00,173 UNDERSTANDING OF THINGS, HIS 174 00:06:00,173 --> 00:06:01,908 REALLY RAPID ABILITY TO ASSESS 175 00:06:01,908 --> 00:06:03,776 THE SIGNAL FROM THE NOISE, AND I 176 00:06:03,776 --> 00:06:05,178 THINK WHEN HE LEFT THE NIH, IT 177 00:06:05,178 --> 00:06:07,146 WAS A REAL LOSS FOR US. 178 00:06:07,146 --> 00:06:10,650 SO WELCOME BACK. 179 00:06:10,650 --> 00:06:13,920 SO MY PART OF THE TALK IS 180 00:06:13,920 --> 00:06:15,521 PERHAPS IN SOME WAYS SIMPLER, 181 00:06:15,521 --> 00:06:16,789 IT'S JUST TO TELL YOU HOW BAD IT 182 00:06:16,789 --> 00:06:17,857 IS. 183 00:06:17,857 --> 00:06:19,959 JUST TO EXPLAIN HOW DIABOLICAL 184 00:06:19,959 --> 00:06:21,494 THIS VIRUS REALLY IS. 185 00:06:21,494 --> 00:06:22,795 AND I'M GRATEFUL FOR THE 186 00:06:22,795 --> 00:06:26,399 INVITATION TO SPEAK TODAY. 187 00:06:26,399 --> 00:06:28,701 MY DISCLOSURE SLIDE, I WANT TO 188 00:06:28,701 --> 00:06:30,236 ELIMINATE HEPATITIS D. 189 00:06:30,236 --> 00:06:31,537 I'M OBSESSED WITH LIVER DISEASE 190 00:06:31,537 --> 00:06:32,672 AND COFFEE IS ANOTHER OBSESSION 191 00:06:32,672 --> 00:06:34,607 THAT WE -- WE CALL THAT A GOOD 192 00:06:34,607 --> 00:06:36,509 START TO THE DAY, BUT COFFEE -- 193 00:06:36,509 --> 00:06:37,677 I DON'T HAVE ANYTHING FINANCIAL 194 00:06:37,677 --> 00:06:39,412 TO DECLARE. 195 00:06:39,412 --> 00:06:40,947 FROM MY PART OF THE TALK, WE'RE 196 00:06:40,947 --> 00:06:42,381 GOING TO UNDERSTAND THE 197 00:06:42,381 --> 00:06:43,616 DIFFICULTY IN IDENTIFYING 198 00:06:43,616 --> 00:06:45,118 PATIENTS INFECTED WITH HEPATITIS 199 00:06:45,118 --> 00:06:46,452 D, AND WE'RE GOING TO UNDERSTAND 200 00:06:46,452 --> 00:06:48,488 HOW TO APPROACH PATIENTS 201 00:06:48,488 --> 00:06:51,224 INFECTED WITH HEPATITIS D. 202 00:06:51,224 --> 00:06:52,358 SO PERHAPS WE COULD START WITH 203 00:06:52,358 --> 00:06:55,061 WHAT IS HEPATITIS D. 204 00:06:55,061 --> 00:06:57,997 IT'S A FANTASTIC STORY. 205 00:06:57,997 --> 00:07:01,834 THTHE DISCOVERY RELATES TO A LOT 206 00:07:01,834 --> 00:07:06,005 OF SEX, INTRIGUE, SERENDIPITY, 207 00:07:06,005 --> 00:07:08,841 UNEXPECTED FINDINGS AND REALLY 208 00:07:08,841 --> 00:07:09,809 DR. ROSETTA'S BRILLIANCE WAS IN 209 00:07:09,809 --> 00:07:12,979 NOT LETTING GO AND SORT OF 210 00:07:12,979 --> 00:07:14,580 PURSUING IT VERY DOGGEDLY AND 211 00:07:14,580 --> 00:07:15,448 UNDERSTANDING THAT THERE WAS 212 00:07:15,448 --> 00:07:15,982 SOMETHING DIFFERENT. 213 00:07:15,982 --> 00:07:20,019 AND THIS IS THE FIRST 214 00:07:20,019 --> 00:07:22,188 DESCRIPTION IN GUT, 1977, 48 215 00:07:22,188 --> 00:07:24,390 YEARS AGO, AND 216 00:07:24,390 --> 00:07:25,458 IMMUNOFLUORESCENCE DETECTION OF 217 00:07:25,458 --> 00:07:28,861 NEW ANTIGEN ANTIBODY SYSTEM, 218 00:07:28,861 --> 00:07:29,362 DELTA FOR DIFFERENT. 219 00:07:29,362 --> 00:07:30,663 THERE WAS NO HEPATITIS C AT THE 220 00:07:30,663 --> 00:07:32,265 TIME SO IT WASN'T THE NEXT 221 00:07:32,265 --> 00:07:33,232 LETTER IN THE ALPHABET. 222 00:07:33,232 --> 00:07:35,001 IT WAS DELTA FOR DIFFERENT. 223 00:07:35,001 --> 00:07:37,170 ASSOCIATED TO HEPATITIS B VIRUS 224 00:07:37,170 --> 00:07:40,306 IN LIVER AND IN SERUM OF 225 00:07:40,306 --> 00:07:41,274 HEPATITIS B ANTIGEN CARRIERS. 226 00:07:41,274 --> 00:07:43,442 WHAT HAPPENED IS THERE WAS A LOT 227 00:07:43,442 --> 00:07:45,378 OF RECONSTRUCTION IN NAPLES AT 228 00:07:45,378 --> 00:07:48,714 THAT TIME, AND IN THE 60s, AND 229 00:07:48,714 --> 00:07:52,618 A LOT OF WOMEN FELT THAT -- FROM 230 00:07:52,618 --> 00:07:53,786 EASTERN EUROPE FELT THAT THOSE 231 00:07:53,786 --> 00:07:56,222 MEN IN NAPLES, THOSE 232 00:07:56,222 --> 00:07:57,089 CONSTRUCTION WORKERS MIGHT BE 233 00:07:57,089 --> 00:07:58,591 LONELY SO THEY WENT TO KEEP THEM 234 00:07:58,591 --> 00:07:59,492 COMPANY, AND AT THE SAME TIME, 235 00:07:59,492 --> 00:08:01,027 THERE WAS THIS MASSIVE OUTBREAK 236 00:08:01,027 --> 00:08:03,329 OF MORE SEVERE HEPATITIS. 237 00:08:03,329 --> 00:08:06,599 HEPATITIS B WAS ALREADY ENDEMIC, 238 00:08:06,599 --> 00:08:07,800 AND THIS OCCURRED ON TOP OF 239 00:08:07,800 --> 00:08:09,902 THAT. 240 00:08:09,902 --> 00:08:13,940 AND WHEN DR. RIZZETTO -- HE WAS 241 00:08:13,940 --> 00:08:15,575 DOING STAINING OF HEPATITIS B IN 242 00:08:15,575 --> 00:08:17,877 THE LIVER AND WHEN HE RAN OUT OF 243 00:08:17,877 --> 00:08:19,712 PATIENT SERA WHICH HE USED TO 244 00:08:19,712 --> 00:08:21,681 STAIN THE LIVERS, HE GOT A FRESH 245 00:08:21,681 --> 00:08:22,815 BATCH AND IT HAPPENED TO BE FROM 246 00:08:22,815 --> 00:08:24,417 A PATIENT THAT JUST HAD DELTA. 247 00:08:24,417 --> 00:08:26,519 AND THEN HE NOTICED THAT SOME OF 248 00:08:26,519 --> 00:08:27,854 THE PATIENTS HAD DIFFERENT 249 00:08:27,854 --> 00:08:29,455 STAINING IN THEIR LIVERS, WHICH 250 00:08:29,455 --> 00:08:33,159 WAS THE DELTA. 251 00:08:33,159 --> 00:08:34,694 HE INITIALLY WASN'T SURE IF IT 252 00:08:34,694 --> 00:08:35,928 WAS AUTOIMMUNE HEPATITIS OR NOT 253 00:08:35,928 --> 00:08:39,732 AND HE CAME TO A YOUNG 254 00:08:39,732 --> 00:08:42,935 RESEARCHER HERE, DR. JAY 255 00:08:42,935 --> 00:08:45,304 HOFFNAGEL, HE MENTIONED HE HAD 256 00:08:45,304 --> 00:08:49,475 THIS AND DR. HOFFNAGEL SAID IN 257 00:08:49,475 --> 00:08:51,043 BUILDING 7 THEY HAVE CHIMPS, WHY 258 00:08:51,043 --> 00:08:52,511 DON'T YOU PUT IT INTO THE CLIM 259 00:08:52,511 --> 00:08:52,778 PS? 260 00:08:52,778 --> 00:08:57,984 CHIMPS? 261 00:08:57,984 --> 00:08:59,318 AGAIN, NIH PLAYED A PIVOTAL 262 00:08:59,318 --> 00:09:00,319 ROLE. 263 00:09:00,319 --> 00:09:02,588 SO YOU'RE GOING TO HEAR THIS 264 00:09:02,588 --> 00:09:06,192 AGAIN, BUT THIS SAID ENOUGH. 265 00:09:06,192 --> 00:09:07,426 WHENEVER WE TALK ABOUT HEPATITIS 266 00:09:07,426 --> 00:09:09,595 D, WE HAVE TO STATE THE 267 00:09:09,595 --> 00:09:12,098 VACCINATION FOR HEPATITIS B IS 268 00:09:12,098 --> 00:09:13,299 THE ULTIMATE CURE FOR HEPATITIS 269 00:09:13,299 --> 00:09:13,733 D. 270 00:09:13,733 --> 00:09:16,068 BECAUSE HEPATITIS D CANNOT EXIST 271 00:09:16,068 --> 00:09:17,136 WITHOUT HEPATITIS B, AND IF YOU 272 00:09:17,136 --> 00:09:18,704 ELIMINATE B, YOU WOULD ELIMINATE 273 00:09:18,704 --> 00:09:18,905 D. 274 00:09:18,905 --> 00:09:20,539 THERE IS NO VACCINE FOR 275 00:09:20,539 --> 00:09:24,143 HEPATITIS D. 276 00:09:24,143 --> 00:09:25,511 WE SHOULD START PERHAPS WITH THE 277 00:09:25,511 --> 00:09:27,480 BAD NEWS. 278 00:09:27,480 --> 00:09:29,181 WHAT IS IT ABOUT HEPATITIS D 279 00:09:29,181 --> 00:09:31,150 THAT'S SO DIFFERENT? 280 00:09:31,150 --> 00:09:32,785 WELL, THERE'S A MUCH FASTER 281 00:09:32,785 --> 00:09:34,520 PROGRESSION TO CIRRHOSIS THAN IN 282 00:09:34,520 --> 00:09:37,556 HEPATITIS B OR HEPATITIS C AND 283 00:09:37,556 --> 00:09:40,793 HEPATITIS C IS ROUGHLY 20% AT 20 284 00:09:40,793 --> 00:09:42,395 YEARS, HEPATITIS B, 30% LIFETIME 285 00:09:42,395 --> 00:09:42,828 RISK. 286 00:09:42,828 --> 00:09:45,932 FOR DELTA, IT'S 10 TO 15% WITHIN 287 00:09:45,932 --> 00:09:49,001 TWO YEARS, 70 TO 90% OVER 10 288 00:09:49,001 --> 00:09:49,302 YEARS. 289 00:09:49,302 --> 00:09:50,503 I ACTUALLY THINK THAT MAY BE A 290 00:09:50,503 --> 00:09:52,138 LITTLE BIT OF AN OVERESTIMATE, 291 00:09:52,138 --> 00:09:54,874 BUT STILL, IT'S DRAMATIC. 292 00:09:54,874 --> 00:09:57,843 THE INCREASED RISK OF LIVER 293 00:09:57,843 --> 00:10:00,713 CANCER OR CARCINOMA COMPARED TO 294 00:10:00,713 --> 00:10:02,181 HEPATITIS B ALONE IS THREE TO 295 00:10:02,181 --> 00:10:03,950 FIVE FOLD AND THE MORTALITY IS 296 00:10:03,950 --> 00:10:05,051 INCREASED MORE THAN TWOFOLD. 297 00:10:05,051 --> 00:10:10,823 SO IT'S DEFINITELY DIFFERENT. 298 00:10:10,823 --> 00:10:13,059 SO WHY DO WE TREAT, WHY ARE 299 00:10:13,059 --> 00:10:14,226 LOOKING FOR THERAPIES, WHY DOES 300 00:10:14,226 --> 00:10:15,094 IT MATTER? 301 00:10:15,094 --> 00:10:16,095 WELL, I'M NOT GOING TO TALK 302 00:10:16,095 --> 00:10:17,964 ABOUT THERAPIES OTHER THAN TO 303 00:10:17,964 --> 00:10:20,466 SHOW YOU THIS. 304 00:10:20,466 --> 00:10:22,902 AT THE CLINICAL CENTER, 13 305 00:10:22,902 --> 00:10:26,605 PATIENTS WERE GIVEN 306 00:10:26,605 --> 00:10:28,774 PEGINTERFERON FOR FIVE YEARS. 307 00:10:28,774 --> 00:10:32,611 30 CONVERTED TO ANTIHBs WITHIN 308 00:10:32,611 --> 00:10:33,913 FIVE YEARS, AND AFTER NINE YEARS 309 00:10:33,913 --> 00:10:36,782 OF FOLLOW-UP, 6 OF THE 310 00:10:36,782 --> 00:10:39,151 7 RESPONDERS WERE ALIVE AND 1 OF 311 00:10:39,151 --> 00:10:40,720 5 OF THE NON-RESPONDERS WERE 312 00:10:40,720 --> 00:10:41,787 ALIVE, SO TREATMENT MAKES A 313 00:10:41,787 --> 00:10:42,655 DIFFERENCE. 314 00:10:42,655 --> 00:10:45,291 AND PERHAPS MOST EXCITINGLY WAS 315 00:10:45,291 --> 00:10:50,863 SOMETHING PUBLISHED IN 1999. 316 00:10:50,863 --> 00:10:52,098 A SINGLE PATIENT WITH DELTA WAS 317 00:10:52,098 --> 00:10:53,733 TREATED WITH INTERFERON FOR 12 318 00:10:53,733 --> 00:10:54,500 YEARS. 319 00:10:54,500 --> 00:10:56,235 CLEAR DELTA BUT MOST 320 00:10:56,235 --> 00:10:57,837 IMPORTANTLY, WENT FROM CIRRHOSIS 321 00:10:57,837 --> 00:10:58,738 TO NORMAL. 322 00:10:58,738 --> 00:11:00,373 AND HERE'S THE HISTOLOGY. 323 00:11:00,373 --> 00:11:10,916 YOU CAN SEE IN PANEL A, PANEL A, 324 00:11:15,221 --> 00:11:17,023 YOU SEE THE SMALL NODULES OF 325 00:11:17,023 --> 00:11:18,758 LIVER TISSUE SURROUNDED BY BLUE 326 00:11:18,758 --> 00:11:24,497 GUFIBROTIC TISSUE. 327 00:11:24,497 --> 00:11:26,432 IN D, IT DOESN'T SAY CIRRHOSIS 328 00:11:26,432 --> 00:11:28,934 IS GONE, IT SAYS NO FIBROSIS WAS 329 00:11:28,934 --> 00:11:29,702 DETECTED. 330 00:11:29,702 --> 00:11:30,803 AND THAT'S OUR AIM. 331 00:11:30,803 --> 00:11:32,671 WE WANT TO GO FROM PANEL A TO 332 00:11:32,671 --> 00:11:34,073 PANEL D. 333 00:11:34,073 --> 00:11:35,374 SO THE WHY. 334 00:11:35,374 --> 00:11:39,111 WE WANT TO DECREASE DEATH, WHICH 335 00:11:39,111 --> 00:11:40,646 IS CAUSED BY HCC OR CIRRHOSIS, 336 00:11:40,646 --> 00:11:42,648 AND WE WANT TO INCREASE 337 00:11:42,648 --> 00:11:44,717 HEPATITIS B SURFACE ANTIGEN ZERO 338 00:11:44,717 --> 00:11:45,985 CONVERSION, WE WANT THE PATIENTS 339 00:11:45,985 --> 00:11:48,087 TO LOSE HEPATITIS B SO THAT THEY 340 00:11:48,087 --> 00:11:50,723 CAN'T GET D AND THE D CAN'T 341 00:11:50,723 --> 00:11:53,459 PROPAGATE, AND IDEALLY WE'D LIKE 342 00:11:53,459 --> 00:11:55,728 THEM TO LOSE HEPATITIS D RNA. 343 00:11:55,728 --> 00:11:57,163 THAT'S AN ASCENDING LIST OF 344 00:11:57,163 --> 00:11:57,496 SURROGATES. 345 00:11:57,496 --> 00:11:59,999 IF YOU GET RID OF THE RNA, GET 346 00:11:59,999 --> 00:12:02,635 RID OF THE HEPATITIS B, GET RID 347 00:12:02,635 --> 00:12:04,470 OF THE CIRRHOSIS, GET RID OF THE 348 00:12:04,470 --> 00:12:06,572 CANCER, GET RID OF THE DEATH. 349 00:12:06,572 --> 00:12:11,911 JUST TO SHOW YOU HOW MUCH HEAP 350 00:12:11,911 --> 00:12:16,315 HEPATITIS D PUNCHES ABOVE ITS 351 00:12:16,315 --> 00:12:17,716 WEIGHT, IN THE EUROPEAN 352 00:12:17,716 --> 00:12:21,654 TRANSPLANT REGISTRY, 25% OF 353 00:12:21,654 --> 00:12:22,855 TRANSPLANTED PATIENTS WITH 354 00:12:22,855 --> 00:12:26,025 HEPATITIS B HAVE HEPATITIS D. 355 00:12:26,025 --> 00:12:27,893 SO IT PUNCHES WAY ABOVE ITS 356 00:12:27,893 --> 00:12:32,765 WEIGHT. 357 00:12:32,765 --> 00:12:34,200 LET'S TALK ABOUT EPIDEMIOLOGY 358 00:12:34,200 --> 00:12:35,267 BECAUSE THAT REALLY MATTERS AS 359 00:12:35,267 --> 00:12:36,135 YOU'LL SEE. 360 00:12:36,135 --> 00:12:37,770 EPIDEMIOLOGY IS VERY CLOUDED BY 361 00:12:37,770 --> 00:12:40,372 WHETHER STUDIES USE ANTIBODY OR 362 00:12:40,372 --> 00:12:43,242 VIRUS, WHETHER THEY ASSESSED THE 363 00:12:43,242 --> 00:12:44,877 PRESENCE OF HEPATITIS D IN 364 00:12:44,877 --> 00:12:48,047 TERTIARY CARE CENTERS, IN HOT 365 00:12:48,047 --> 00:12:49,582 SPOTS, IN PRIMARY CARE SETTINGS, 366 00:12:49,582 --> 00:12:53,185 IN BLOOD DONORS. IN EACH 367 00:12:53,185 --> 00:12:54,086 SETTING THERE'S DIFFERENT 368 00:12:54,086 --> 00:12:55,187 PROBABILITY OF FINDING HEPATITIS 369 00:12:55,187 --> 00:12:56,388 D. 370 00:12:56,388 --> 00:12:57,089 TREMENDOUS ASSAY VARIABILITY. 371 00:12:57,089 --> 00:12:59,959 AND I'M GOING TO COME BACK TO 372 00:12:59,959 --> 00:13:03,129 THAT. 373 00:13:03,129 --> 00:13:05,331 AND THE MOST IMPORTANT THING, 374 00:13:05,331 --> 00:13:11,036 JUST THE IGNORANCE AND LACK OF 375 00:13:11,036 --> 00:13:11,904 TESTING. 376 00:13:11,904 --> 00:13:13,072 "HOWEVER, DESPITE 40 YEARS, IT 377 00:13:13,072 --> 00:13:15,174 WAS 40 YEARS AT THE TIME, OF 378 00:13:15,174 --> 00:13:15,941 EPIDEMIOLOGICAL SURVEYS, THE 379 00:13:15,941 --> 00:13:17,309 GLOBAL NUMBER OF INFECTED 380 00:13:17,309 --> 00:13:18,544 PATIENTS REMAINS UNDEFINED. 381 00:13:18,544 --> 00:13:21,847 48 TO 60 MILLION, 62 TO 382 00:13:21,847 --> 00:13:22,348 72 MILLION, 12 MILLION. 383 00:13:22,348 --> 00:13:23,616 THAT'S VERY DIFFERENT. 384 00:13:23,616 --> 00:13:25,284 THESE WIDELY DIFFERENT FIGURES 385 00:13:25,284 --> 00:13:27,086 EMPHASIZE THE HETEROGENEITY OF 386 00:13:27,086 --> 00:13:28,954 REPORTS ON HEPATITIS D, AND A 387 00:13:28,954 --> 00:13:31,123 LACK OF SUFFICIENT QUALITY DATA. 388 00:13:31,123 --> 00:13:33,325 THE EMPHASIS IS MINE. 389 00:13:33,325 --> 00:13:34,627 THUS, INADEQUATE SCREENING, 390 00:13:34,627 --> 00:13:35,494 TECHNICAL LIMITATIONS AND LACK 391 00:13:35,494 --> 00:13:41,200 OF TESTING ARE PROBLEMS. 392 00:13:41,200 --> 00:13:43,269 IF WE LOOK AT THE GLOBAL MAP, 393 00:13:43,269 --> 00:13:45,671 WHAT YOU CAN SEE IS HOT SPOTS. 394 00:13:45,671 --> 00:13:47,306 THE FIRST THING THAT JUMPS OUT 395 00:13:47,306 --> 00:13:49,074 IS AREAS WHERE THERE'S A LOT OF 396 00:13:49,074 --> 00:13:50,075 HEPATITIS D. 397 00:13:50,075 --> 00:13:52,344 THESE AREAS, MONGOLIA, THE DELTA 398 00:13:52,344 --> 00:13:54,780 BELT AND PAKISTAN, PARTS OF AFER 399 00:13:54,780 --> 00:13:57,082 AFRICA, THE AMAZON BASIN, WHERE 400 00:13:57,082 --> 00:13:59,485 THERE'S A VERY HIGH PREVALENCE 401 00:13:59,485 --> 00:14:02,755 OF HEPATITIS D. 402 00:14:02,755 --> 00:14:04,290 IT'S NOT UNDERSTOOD WHY. 403 00:14:04,290 --> 00:14:08,227 PARTIALLY BUT NOT COMPLETED OF . 404 00:14:08,227 --> 00:14:10,296 YOU CAN SEE THERE'S QUITE A 405 00:14:10,296 --> 00:14:13,799 RANGE OF PREVALENCE, AND LASTLY, 406 00:14:13,799 --> 00:14:14,900 THERE'S DIFFERENT GENOTYPES. 407 00:14:14,900 --> 00:14:16,101 AND THIS IS IMPORTANT FOR A 408 00:14:16,101 --> 00:14:18,504 NUMBER OF REASONS. 409 00:14:18,504 --> 00:14:22,408 THE GENOTYPE ONE IS FOUND 410 00:14:22,408 --> 00:14:24,310 GLOBALLY, 2 AND 4 IN ASIA, # IN 411 00:14:24,310 --> 00:14:27,580 SOUTH MAYOR KA, BUT 5, 6, 7 AND 412 00:14:27,580 --> 00:14:28,447 8 ARE FOUND IN AFRICA. 413 00:14:28,447 --> 00:14:30,549 THE PROBLEM WITH 5, 6, 7 AND 414 00:14:30,549 --> 00:14:31,850 8 ARE THEY MOST DIVERGENT, THE 415 00:14:31,850 --> 00:14:33,485 LAST TO BE FOUND A LOT OF THE 416 00:14:33,485 --> 00:14:35,154 OLDER ASSAYS DON'T DETECT THEM. 417 00:14:35,154 --> 00:14:36,989 SO IN PATIENTS FROM AFRICA, WHEN 418 00:14:36,989 --> 00:14:38,424 THEY COME TO THE WEST OFTEN THE 419 00:14:38,424 --> 00:14:41,427 DELTA IS MISSED AND IN A LOT OF 420 00:14:41,427 --> 00:14:42,394 EPIDEMIOLOGIC SURVEY, DELTA IS 421 00:14:42,394 --> 00:14:42,895 MISSED. 422 00:14:42,895 --> 00:14:45,831 WHAT ABOUT AMERICA? 423 00:14:45,831 --> 00:14:47,900 IN NORTHERN CALIFORNIA, 1191 424 00:14:47,900 --> 00:14:52,304 PATIENTS TESTED, AND 499 FOR 425 00:14:52,304 --> 00:14:52,838 HEPATITIS B. 426 00:14:52,838 --> 00:14:56,809 OF THEM, ALMOST 500 WERE TESTED 427 00:14:56,809 --> 00:14:58,777 FOR HEPATITIS B, 42 PEST, THAT 428 00:14:58,777 --> 00:15:02,481 42%, MUCHHIGHER THAN THE TYPICAE 429 00:15:02,481 --> 00:15:03,716 IF YOU LOOK IN STUDIES LIKE 430 00:15:03,716 --> 00:15:04,883 THIS, BUT I'M USING THIS TO SHOW 431 00:15:04,883 --> 00:15:06,418 YOU THAT 8% OF THE PATIENTS 432 00:15:06,418 --> 00:15:09,255 TESTED WERE POSITIVE. 433 00:15:09,255 --> 00:15:12,858 IN A VETERAN POPULATION DONE BY 434 00:15:12,858 --> 00:15:14,627 TATIANA KUSHNER, WHO WAS A 435 00:15:14,627 --> 00:15:16,495 FELLOW AT THE TIME, AND FOR THE 436 00:15:16,495 --> 00:15:18,063 FELLOWS LISTENING, OR MAYBE NOT 437 00:15:18,063 --> 00:15:22,368 LILISTENING, TATIANA WAS A FELLW 438 00:15:22,368 --> 00:15:24,336 AT U-PENN, AND I GAVE A TALK, 439 00:15:24,336 --> 00:15:26,205 AND I WAS TALKING -- SAID HOW 440 00:15:26,205 --> 00:15:28,407 IMPORTANT I THINK DELTA IS AND 441 00:15:28,407 --> 00:15:29,541 SHE SAID, BUT THAT'S VERY NICE 442 00:15:29,541 --> 00:15:31,010 BUT WE JUST DON'T SEE ANY IN 443 00:15:31,010 --> 00:15:31,543 AMERICA. 444 00:15:31,543 --> 00:15:32,878 AND I SAID THAT'S BECAUSE YOU 445 00:15:32,878 --> 00:15:33,846 DON'T TEST. 446 00:15:33,846 --> 00:15:35,214 AND WE GOT INTO THIS WHOLE 447 00:15:35,214 --> 00:15:35,614 DISCUSSION. 448 00:15:35,614 --> 00:15:37,216 AND AS A FELLOW, SHE THEN WENT 449 00:15:37,216 --> 00:15:39,151 TO THE U.S. VETERAN POPULATION 450 00:15:39,151 --> 00:15:42,855 DATABASE AND SHE SHOWED THAT 25 451 00:15:42,855 --> 00:15:44,823 THOWL 600 PATIENTS WERE FOUND TO 452 00:15:44,823 --> 00:15:46,458 HAVE HEPATITIS B. 453 00:15:46,458 --> 00:15:48,560 ONLY 8 1/2% WERE TESTED, A 454 00:15:48,560 --> 00:15:53,065 LITTLE BIT OVER 2,000, AND 73, 455 00:15:53,065 --> 00:15:54,900 THAT'S 3.4%, WERE POSITIVE FOR 456 00:15:54,900 --> 00:15:56,602 HEPATITIS D. 457 00:15:56,602 --> 00:15:57,803 AND IF WE THINK THAT THESE ARE 458 00:15:57,803 --> 00:15:59,138 THE PATIENTS THAT ARE GOING TO 459 00:15:59,138 --> 00:16:00,339 GET TRANSPLANTED AND THESE ARE 460 00:16:00,339 --> 00:16:01,473 THE PATIENTS WHO ARE GOING TO 461 00:16:01,473 --> 00:16:03,275 DIE, THAT'S A LOT. 462 00:16:03,275 --> 00:16:05,244 3.4%. 463 00:16:05,244 --> 00:16:07,546 AND ONLY 8 1/2% TESTED IS NOT 464 00:16:07,546 --> 00:16:08,113 ENOUGH. 465 00:16:08,113 --> 00:16:12,251 AND IT WAS PUBLISHED IN J 466 00:16:12,251 --> 00:16:13,485 HEPATOLOGY, NICE FELLOW PROJECT. 467 00:16:13,485 --> 00:16:14,553 WHAT ABOUT THE EPIDEMIOLOGY? 468 00:16:14,553 --> 00:16:18,724 A PAPER FROM HERE LOOKING AT 588 469 00:16:18,724 --> 00:16:21,260 PATIENTS, SHOWED INACTIVE 470 00:16:21,260 --> 00:16:22,528 HEPATITIS B WITH A LEVEL LESS 471 00:16:22,528 --> 00:16:22,895 THAN 2,000. 472 00:16:22,895 --> 00:16:24,063 WE'RE GOING TO COME BACK TO 473 00:16:24,063 --> 00:16:24,630 THAT. 474 00:16:24,630 --> 00:16:27,966 AN ELEVATED ALT WITH A LOW LEVEL 475 00:16:27,966 --> 00:16:29,001 HEPATITIS B SHOULD MAKE YOU 476 00:16:29,001 --> 00:16:30,302 THINK ABOUT DELTA. 477 00:16:30,302 --> 00:16:31,837 AND THEN THE CLASSIC RISK 478 00:16:31,837 --> 00:16:34,239 FACTORS IN NORTH AMERICA, 479 00:16:34,239 --> 00:16:36,875 INTRAVENOUS DRUG USE, AND 480 00:16:36,875 --> 00:16:38,510 HEPATITIS D ENDEMIC COUNTRY OF 481 00:16:38,510 --> 00:16:39,178 ORIGIN. 482 00:16:39,178 --> 00:16:39,912 REMEMBER THOSE HOT SPOTS THAT I 483 00:16:39,912 --> 00:16:41,747 SHOWED YOU, THOSE RED AREAS ON 484 00:16:41,747 --> 00:16:42,214 THE MAP? 485 00:16:42,214 --> 00:16:43,649 IF PEOPLE COME FROM THOSE AREA, 486 00:16:43,649 --> 00:16:45,617 VERY LIKELY TO HAVE HEPATITIS D 487 00:16:45,617 --> 00:16:47,152 WITH HEPATITIS B. 488 00:16:47,152 --> 00:16:50,589 AND IF WE LOOK AT THE 489 00:16:50,589 --> 00:16:52,057 GUIDELINES, EASEL SAYS TEST 490 00:16:52,057 --> 00:16:53,625 EVERYONE, THAT'S THE EUROPEAN 491 00:16:53,625 --> 00:16:54,593 ASSOCIATION FOR THE STUDY OF 492 00:16:54,593 --> 00:16:56,128 LIVER DISEASE, EVERYONE HAS 493 00:16:56,128 --> 00:16:56,662 HEPATITIS B. 494 00:16:56,662 --> 00:17:01,367 SHOULD BE CHECKED FOR D, C, AND 495 00:17:01,367 --> 00:17:02,234 HIV. 496 00:17:02,234 --> 00:17:03,602 APASL OR THE ASIAN GUIDELINES 497 00:17:03,602 --> 00:17:04,903 SAID THE SAME. 498 00:17:04,903 --> 00:17:08,240 BUT THE AMERICAN GUIDELINES SAY 499 00:17:08,240 --> 00:17:10,008 INACTIVE HEPATITIS B OR PEOPLE 500 00:17:10,008 --> 00:17:10,542 AT RISK. 501 00:17:10,542 --> 00:17:11,910 THE PROBLEM IS WE DON'T FOLLOW 502 00:17:11,910 --> 00:17:15,814 THOSE GUIDELINES, AND I WANT TO 503 00:17:15,814 --> 00:17:19,184 USE ONE PATIENT TO ILLUSTRATE 504 00:17:19,184 --> 00:17:20,386 THAT. 505 00:17:20,386 --> 00:17:22,921 49-YEAR-OLD MALE BORN IN IDAHO, 506 00:17:22,921 --> 00:17:25,190 JOHN PUBLIC, MARRIED WITH TWO 507 00:17:25,190 --> 00:17:26,525 CHILDREN, OUTSTANDING CITIZEN, 508 00:17:26,525 --> 00:17:27,626 INVOLVED IN HIS COMMUNITY. 509 00:17:27,626 --> 00:17:31,897 HE HAD HIS COLONOSCOPY AND HIS 510 00:17:31,897 --> 00:17:32,765 ASTUTE GASTROENTEROLOGIST 511 00:17:32,765 --> 00:17:33,732 NOTICED HE WAS CIRRHOTIC AND 512 00:17:33,732 --> 00:17:36,802 NOTICE THAT HIS HEPATITIS B WAS 513 00:17:36,802 --> 00:17:38,203 ACTIVE, 150,000, AND E ANTIGEN 514 00:17:38,203 --> 00:17:38,470 POSITIVE. 515 00:17:38,470 --> 00:17:40,305 AND HE TREATED HIM, BUT THEN HE 516 00:17:40,305 --> 00:17:42,274 WENT ON TO DEVELOP 517 00:17:42,274 --> 00:17:42,708 CHOLANGIOCARCINOMA. 518 00:17:42,708 --> 00:17:44,676 HE HAD MULTIPLE, MULTIPLE 519 00:17:44,676 --> 00:17:46,211 ENCOUNTERS WITH THE MEDICAL 520 00:17:46,211 --> 00:17:49,148 SYSTEM, BUT IT TOOK AN ASTUTE 521 00:17:49,148 --> 00:17:51,183 ONCOLOGIST TO CHECK HIM AND FIND 522 00:17:51,183 --> 00:17:54,319 THAT HE'S HEPATITIS D POSITIVE. 523 00:17:54,319 --> 00:17:56,822 NO ONE KNEW ABOUT HIS YOUTHFUL 524 00:17:56,822 --> 00:17:57,990 INDISCRETIONS, NOT EVEN HIS 525 00:17:57,990 --> 00:18:00,192 WIFE. 526 00:18:00,192 --> 00:18:02,928 SO IT DOESN'T MATTER IF YOU ASK 527 00:18:02,928 --> 00:18:04,062 OR DON'T ASK. 528 00:18:04,062 --> 00:18:07,433 THI THINK THE IMPORTANT THING IS 529 00:18:07,433 --> 00:18:07,966 TO TEST. 530 00:18:07,966 --> 00:18:09,868 I KNOW HIS STORY IS ANECDOTAL, 531 00:18:09,868 --> 00:18:14,540 BUT THERE'S A NICE PAPER IN J 532 00:18:14,540 --> 00:18:17,709 H EP IN 2014 SHOWING BOTH ARE 533 00:18:17,709 --> 00:18:20,712 DOMINANT, OFTEN IT'S NOT JUST 534 00:18:20,712 --> 00:18:23,081 HEPATITIS B WHICH IS DOMINANT, 535 00:18:23,081 --> 00:18:24,082 SORRY, HEPATITIS D THAT'S 536 00:18:24,082 --> 00:18:25,484 DOMINANT, WHICH IS THE BLUE IN 537 00:18:25,484 --> 00:18:26,485 THAT PIE CHART. 538 00:18:26,485 --> 00:18:28,587 AND IF YOU LOOK AT A SECOND 539 00:18:28,587 --> 00:18:29,688 PAPER, WHICH IS A LITTLE BIT 540 00:18:29,688 --> 00:18:33,158 MORE COMPLEX, ESSENTIALLY THE 541 00:18:33,158 --> 00:18:34,726 SAME THING. 542 00:18:34,726 --> 00:18:36,562 THE HEPATITIS D DOMINANCE IS THE 543 00:18:36,562 --> 00:18:39,198 BLUE AND THE ORANGE. 544 00:18:39,198 --> 00:18:41,667 SO 44% AND 39% OF PATIENTS IN 545 00:18:41,667 --> 00:18:45,871 TWO SERIES, TWO LARGE SERIES, DO 546 00:18:45,871 --> 00:18:48,607 NOT HAVE HEPATITIS B AS 547 00:18:48,607 --> 00:18:49,675 DOMINANCE, SO IT SHOULDN'T SHOP 548 00:18:49,675 --> 00:18:50,342 YOU FROM TESTING. 549 00:18:50,342 --> 00:18:51,543 WHY THE EMPHASIS? 550 00:18:51,543 --> 00:18:54,179 AND IF YOU ALLOW ME TO INVOKE A 551 00:18:54,179 --> 00:18:56,582 PREVIOUS NIH DIRECTOR FROM A 552 00:18:56,582 --> 00:19:00,285 DIFFERENT ERA, IN HIS -- IN 553 00:19:00,285 --> 00:19:02,054 DR. VARMUS' BOOK ABOUT THE ART 554 00:19:02,054 --> 00:19:04,423 AND POLITICS OF SCIENCE, HE 555 00:19:04,423 --> 00:19:05,657 POINTS OUT THAT MANY NOBEL 556 00:19:05,657 --> 00:19:06,692 PRIZES HAVE BEEN GIVEN FOR THE 557 00:19:06,692 --> 00:19:08,160 ABILITY TO MEASURE SOMETHING OR 558 00:19:08,160 --> 00:19:08,594 SEE SOMETHING. 559 00:19:08,594 --> 00:19:10,028 IF YOU CAN'T MEASURE IT, YOU 560 00:19:10,028 --> 00:19:11,296 CAN'T SEE IT, YOU CAN'T STUDY 561 00:19:11,296 --> 00:19:11,463 IT. 562 00:19:11,463 --> 00:19:12,764 YOU HAVE TO BE ABLE TO DETECT IT 563 00:19:12,764 --> 00:19:15,234 AND YOU HAVE TO BE ABLE TO 564 00:19:15,234 --> 00:19:17,836 DETECT IT ACCURATELY. 565 00:19:17,836 --> 00:19:19,638 SO TEST EVERYONE WITH HEPATITIS 566 00:19:19,638 --> 00:19:19,972 B. 567 00:19:19,972 --> 00:19:22,040 AND I WOULD SUGGEST USING AN 568 00:19:22,040 --> 00:19:25,177 ANTIBODY AS A SCREEN AND IN 569 00:19:25,177 --> 00:19:26,745 HEPATITIS D, PCR TO CONFIRM. 570 00:19:26,745 --> 00:19:28,046 THERE ARE NOW COMMERCIALLY 571 00:19:28,046 --> 00:19:31,216 AVAILABLE ASSAYS. 572 00:19:31,216 --> 00:19:33,619 AND IT'S KEY TO CONFIRM WITH THE 573 00:19:33,619 --> 00:19:34,720 PCR, BECAUSE SOME PATIENTS WILL 574 00:19:34,720 --> 00:19:36,822 CLEAR. 575 00:19:36,822 --> 00:19:37,689 OKAY, WHAT NEXT? 576 00:19:37,689 --> 00:19:42,728 LET'S GO BACK TO BASICS. 577 00:19:42,728 --> 00:19:43,595 TRANSMITTED THROUGH BLOOD AND 578 00:19:43,595 --> 00:19:44,396 BODY FLUIDS. 579 00:19:44,396 --> 00:19:46,431 IT'S ACQUIRED IN TWO WAYS, 580 00:19:46,431 --> 00:19:47,332 EITHER COINFECTION, THAT MEANS 581 00:19:47,332 --> 00:19:48,967 YOU GET B AND D TOGETHER, YOU 582 00:19:48,967 --> 00:19:52,371 HAVE SEX OR SHARE NEEDLES WITH 583 00:19:52,371 --> 00:19:54,573 SOMEONE WHO HAS BOTH VIRUSES AND 584 00:19:54,573 --> 00:19:56,275 YOU GET INFECTED WITH BOTH 585 00:19:56,275 --> 00:19:56,808 VIRUSES. 586 00:19:56,808 --> 00:19:58,010 THAT'S OFTEN ACUTE AND OFTEN 587 00:19:58,010 --> 00:19:58,710 VERY SEVERE. 588 00:19:58,710 --> 00:20:02,648 AND THE RISK OF CROW NIS IT IS S 589 00:20:02,648 --> 00:20:03,215 VERY LOW. 590 00:20:03,215 --> 00:20:04,383 IT DEPENDS ON THE AGE OF THE 591 00:20:04,383 --> 00:20:06,451 PERSON BUT IN AN ADULT, IT'S 592 00:20:06,451 --> 00:20:07,786 ABOUT 2%. 593 00:20:07,786 --> 00:20:10,055 THE SECOND IS SUPER INFECTION. 594 00:20:10,055 --> 00:20:12,991 THIS IS OFTEN MISSED, AND 90% OF 595 00:20:12,991 --> 00:20:14,760 THESE PATIENTS BECOME CHRONIC. 596 00:20:14,760 --> 00:20:22,100 REMEMBER THE STORY ABOUT NAPLES, 597 00:20:22,100 --> 00:20:23,502 HEPATITIS SUPERIMPOSED ON TOP OF 598 00:20:23,502 --> 00:20:23,835 THAT? 599 00:20:23,835 --> 00:20:24,836 MOST OF THEM BECAME CHRONIC. 600 00:20:24,836 --> 00:20:25,904 THIS IS WHAT IT LOOKS LIKE. 601 00:20:25,904 --> 00:20:28,440 IN THE TOP CURVE, THE HEPATITIS 602 00:20:28,440 --> 00:20:30,943 B DNA IS THE YELLOW. 603 00:20:30,943 --> 00:20:33,011 THE D RNA IS THAT LITTLE BLUE 604 00:20:33,011 --> 00:20:34,446 BLIP HIDING BETWEEN THE GREY AND 605 00:20:34,446 --> 00:20:35,113 THE YELLOW. 606 00:20:35,113 --> 00:20:37,816 AND THE LT IS THE DOTTED LINE. 607 00:20:37,816 --> 00:20:39,384 AND IF YOU GO TO THE BOTTOM 608 00:20:39,384 --> 00:20:42,788 CURVE, WHICH IS SUPER INFECTION, 609 00:20:42,788 --> 00:20:46,592 THE GREY IS THE HEPATITIS B 610 00:20:46,592 --> 00:20:47,225 SURFACE ANTIGEN. 611 00:20:47,225 --> 00:20:49,227 THE ALT, THAT DOTTED RED LINE 612 00:20:49,227 --> 00:20:51,830 MAKES A LITTLE JUMP UP AND THEN 613 00:20:51,830 --> 00:20:54,566 RE-ADJUST TO A NEW NORMAL HIGHER 614 00:20:54,566 --> 00:21:00,606 BASELINE AND THE HEPATITIS D RNA 615 00:21:00,606 --> 00:21:02,541 TAKES OVER AND BECOMES DOMINANT. 616 00:21:02,541 --> 00:21:04,643 SO IT REALLY INTERESTING BEFORE 617 00:21:04,643 --> 00:21:06,945 WE TALK ABOUT THE VIROLOGY, I 618 00:21:06,945 --> 00:21:08,680 SHOULD POINT OUT THE CLOSEST 619 00:21:08,680 --> 00:21:11,416 RELATIVE TO HEPATITIS D IS THE 620 00:21:11,416 --> 00:21:13,819 PLANT VIROID. 621 00:21:13,819 --> 00:21:18,190 THERE'S NO OTHER VIROID, I USE 622 00:21:18,190 --> 00:21:19,191 THAT WORD BECAUSE IT'S 623 00:21:19,191 --> 00:21:20,492 INCOMPLETE, IT'S NOT REALLY A 624 00:21:20,492 --> 00:21:22,661 VIRUS, IT'S ABSOLUTELY DEPENDENT 625 00:21:22,661 --> 00:21:23,662 ON HEPATITIS B BUT IT STILL 626 00:21:23,662 --> 00:21:24,463 ESTABLISHES DOMINANCE IN MORE 627 00:21:24,463 --> 00:21:26,298 THAN HALF OF PATIENTS. 628 00:21:26,298 --> 00:21:28,133 SO INTERESTING AND SNEAKY. 629 00:21:28,133 --> 00:21:31,536 IT'S A SINGLE NEGATIVE SENSE 630 00:21:31,536 --> 00:21:32,537 RNA. 631 00:21:32,537 --> 00:21:34,206 1700 NUCLEOTIDES, SO TINY. 632 00:21:34,206 --> 00:21:37,142 THE SMALLEST PATHOGENIC VIRUS IN 633 00:21:37,142 --> 00:21:37,376 HUMANS. 634 00:21:37,376 --> 00:21:39,444 THERE ARE OTHER VIRUS, BUT IT'S 635 00:21:39,444 --> 00:21:42,681 THE SMALLEST PATHOGENIC VIRUS. 636 00:21:42,681 --> 00:21:44,216 IT'S COVALENTLY CLOSED AND TAKES 637 00:21:44,216 --> 00:21:45,984 THIS ROD SHAPED STRUCTURE AND IT 638 00:21:45,984 --> 00:21:47,619 WAS PUBLISHED IN SCIENCE IN THE 639 00:21:47,619 --> 00:21:49,888 60s AND IT FORMS MULTIPLE BASE 640 00:21:49,888 --> 00:21:51,123 PAIRS, ALMOST LIKE DNA AND WE'RE 641 00:21:51,123 --> 00:21:52,958 GOING TO COME BACK TO THAT, AND 642 00:21:52,958 --> 00:21:54,292 IT'S SURROUNDED BY HEPATITIS D 643 00:21:54,292 --> 00:21:55,761 LARGE AND SMALL ANTIGEN, IF YOU 644 00:21:55,761 --> 00:21:57,029 LOOK AT THE TOP FIGURE. 645 00:21:57,029 --> 00:21:59,665 AND THEN IT'S ENCASED IN THE 646 00:21:59,665 --> 00:22:00,532 HEPATITIS B ENVELOPE. 647 00:22:00,532 --> 00:22:05,437 HEPATITIS B IS BELOW THAT. 648 00:22:05,437 --> 00:22:06,438 COMPLERK STRUCTURE. 649 00:22:06,438 --> 00:22:07,305 TREMENDOUS PROGRESS HAS BEEN 650 00:22:07,305 --> 00:22:07,806 MADE. 651 00:22:07,806 --> 00:22:09,708 WE NOW UNDERSTAND A LARGE PART 652 00:22:09,708 --> 00:22:11,743 OF THE VIRUS LIFECYCLE. 653 00:22:11,743 --> 00:22:15,347 IT REALLY A TRIUMPH OF MOLECULAR 654 00:22:15,347 --> 00:22:18,684 VIROLOGY AND MOSTLY NIH FUNDING. 655 00:22:18,684 --> 00:22:23,088 TIT'S AN EXAMPLE OF DELAYED 656 00:22:23,088 --> 00:22:24,022 GRATIFICATION BECAUSE IT'S THE 657 00:22:24,022 --> 00:22:25,891 PURSUIT OF SCIENCE WITHOUT 658 00:22:25,891 --> 00:22:28,193 IMMEDIATE OBVIOUS APPLICATION. 659 00:22:28,193 --> 00:22:29,494 WHEN PEOPLE WERE STUDYING AND 660 00:22:29,494 --> 00:22:30,929 LOOKING AT THIS, THEY DIDN'T 661 00:22:30,929 --> 00:22:31,897 UNDERSTAND THEIR INSIGHTS AT THE 662 00:22:31,897 --> 00:22:33,865 TIME WOULD LEAD TO DRUG 663 00:22:33,865 --> 00:22:34,599 DISCOVERY. 664 00:22:34,599 --> 00:22:37,502 AND JUST ONE SMALL THING. 665 00:22:37,502 --> 00:22:44,609 HOST DNA DEPENDENT RNA 666 00:22:44,609 --> 00:22:45,677 POLYMERASES -- TRANSCRIPTION OF 667 00:22:45,677 --> 00:22:47,345 HEPATITIS D ANTIGEN MRNA. 668 00:22:47,345 --> 00:22:48,947 YOU CAN'T DO THAT IN A TEST TUBE 669 00:22:48,947 --> 00:22:50,182 IF YOU TRIED. 670 00:22:50,182 --> 00:22:52,818 RNA DEPENDENT -- RNA POLYMERASES 671 00:22:52,818 --> 00:22:55,087 MAKE RNA FROM RNA TEMPLATE, BUT 672 00:22:55,087 --> 00:22:59,391 HERE YOU'RE TAKING A DNA 673 00:22:59,391 --> 00:23:00,992 DEPENDENT RNA PLER ACE AND USING 674 00:23:00,992 --> 00:23:03,962 TO MAKE RNA FROM RNA. 675 00:23:03,962 --> 00:23:06,465 IT'S PRETTY INTERESTING. 676 00:23:06,465 --> 00:23:08,066 SO LIKE ANY SELF RESPECTING 677 00:23:08,066 --> 00:23:11,169 VIRUS THAT HAS TO GET INTO THE 678 00:23:11,169 --> 00:23:15,107 CELL, A VIROID, IT'S ENCASED IN 679 00:23:15,107 --> 00:23:18,510 HEPATITIS B AND IT GETS IN 680 00:23:18,510 --> 00:23:19,978 THROUGH THE TRANSPORT PROTEIN, 681 00:23:19,978 --> 00:23:22,981 AND ONCE IN THE CELL, REPLICATES 682 00:23:22,981 --> 00:23:25,350 IN THE NUCLEUS, IT'S NEGATIVE 683 00:23:25,350 --> 00:23:27,819 SENSE SO POSITIVE SENSE GETS 684 00:23:27,819 --> 00:23:28,687 TRANSCRIBED. 685 00:23:28,687 --> 00:23:30,422 IT THEN REPLICATES INSIDE THE 686 00:23:30,422 --> 00:23:31,323 NUCLEUS SO WE'RE GOING TO COME 687 00:23:31,323 --> 00:23:32,824 BACK TO THAT IN THE NEXT SLIDE, 688 00:23:32,824 --> 00:23:33,725 WE'RE GOING TO TALK ABOUT THAT 689 00:23:33,725 --> 00:23:43,001 IN A LITTLE BIT MORE DETAIL. 690 00:23:43,001 --> 00:23:44,636 IT'S SENT OUT TO THE CYTOPLASM 691 00:23:44,636 --> 00:23:47,906 WHERE IT'S TRANSLATED INTO 692 00:23:47,906 --> 00:23:51,209 PROTEIN, AND THEN SETTLE BACK 693 00:23:51,209 --> 00:23:55,046 INTO THE NUCLEUS TO FORM THE 694 00:23:55,046 --> 00:23:56,281 RIBONUCLEAR PROTEIN WHICH THEN 695 00:23:56,281 --> 00:23:58,583 GETS SHUTTLED INTO THE NUCLEUS 696 00:23:58,583 --> 00:24:00,485 INTO THE ENDOPLASMIC RETICULUM 697 00:24:00,485 --> 00:24:02,320 TO BE ENCAPSULATED INTO THE 698 00:24:02,320 --> 00:24:03,522 HEPATITIS B ENVELOPE WITH THE 699 00:24:03,522 --> 00:24:05,423 HEPATITIS B SURFACE ANTIGEN, AND 700 00:24:05,423 --> 00:24:08,760 THAT WILL THEN BE SENT OUT OF 701 00:24:08,760 --> 00:24:10,695 THE CELL TO GO INFECT SOME OTHER 702 00:24:10,695 --> 00:24:18,670 CELLS OR SOME OTHER PERSON. 703 00:24:18,670 --> 00:24:21,606 SO I WANT TO FOCUS JUST A LITTLE 704 00:24:21,606 --> 00:24:23,542 BIT ON ONE ASPECT OF REPLICATION 705 00:24:23,542 --> 00:24:26,011 BECAUSE I THINK IT SAYS SO MUCH 706 00:24:26,011 --> 00:24:27,512 ABOUT HOW INTERESTING THIS VIRUS 707 00:24:27,512 --> 00:24:31,249 IS. 708 00:24:31,249 --> 00:24:32,551 THERE ARE TWO PROTEINS. 709 00:24:32,551 --> 00:24:33,885 IT RELIES COMPLETELY, ALL OF 710 00:24:33,885 --> 00:24:35,620 THAT THAT I JUST SHOWED YOU, ALL 711 00:24:35,620 --> 00:24:40,225 OF THIS RELIES ON HOST PROTEINS. 712 00:24:40,225 --> 00:24:40,759 FOR REPLICATION. 713 00:24:40,759 --> 00:24:47,999 THE VIRUS ITSELF DOES VIROID, 714 00:24:47,999 --> 00:24:49,334 ENCODE ANY OF ITS OWN PROTEINS. 715 00:24:49,334 --> 00:24:51,269 IT HAS AN ENZYME BUT IT CLEAVES 716 00:24:51,269 --> 00:24:51,603 ITSELF. 717 00:24:51,603 --> 00:24:54,573 IT HAS A RIBOZYME, THAT'S A PART 718 00:24:54,573 --> 00:24:57,509 OF THE RNA THAT CLEAVES THE RNA 719 00:24:57,509 --> 00:25:05,483 FROM CLOSED TO OPEN ON A LINEAR 720 00:25:05,483 --> 00:25:06,384 STRAND OF RNA. 721 00:25:06,384 --> 00:25:09,087 EVERYTHING ELSE IS COMPLETELY 722 00:25:09,087 --> 00:25:11,423 DEPENDENT DENT ON THE HOST 723 00:25:11,423 --> 00:25:13,024 MACHINERY WHICH EXPLAINS WHY 724 00:25:13,024 --> 00:25:14,492 IT'S BEEN SO DIFFICULT TO COME 725 00:25:14,492 --> 00:25:15,794 UP WITH THERAPIES FOR IT. 726 00:25:15,794 --> 00:25:20,365 THE INITIAL PLUS STRAND HAS AN A 727 00:25:20,365 --> 00:25:22,868 IN CODON 196, WHICH FORMS AN 728 00:25:22,868 --> 00:25:25,937 AMBER STOP CODON, UAG. 729 00:25:25,937 --> 00:25:28,673 AND IT MAKES THIS PROTEIN WITH 730 00:25:28,673 --> 00:25:32,844 THWHERE THAT STOP CODON IS THE 731 00:25:32,844 --> 00:25:34,479 SMALL DELTA ANTIGEN AND THAT WAS 732 00:25:34,479 --> 00:25:38,083 REQUIRED FOR REPLICATION. 733 00:25:38,083 --> 00:25:40,485 THERE'S A HOST DEFENSE PROTEIN 734 00:25:40,485 --> 00:25:46,391 ENZYME CALLED AD1 AND THIS IS 735 00:25:46,391 --> 00:25:47,259 INDUCED BY INTERFERON. 736 00:25:47,259 --> 00:25:50,328 SO THIS IS INDUCED BY OUR 737 00:25:50,328 --> 00:25:54,299 DEFENSE AGAINST THE VIRUS. 738 00:25:54,299 --> 00:25:57,002 THIS PROTEIN, THIS ENZYME 739 00:25:57,002 --> 00:25:59,304 FORMALLY CAUSES CHAOS MUTATIONS. 740 00:25:59,304 --> 00:26:01,273 IT CAUSES MUTATIONS IN 741 00:26:01,273 --> 00:26:03,141 RETROVIRUSES THAT WILL MAKE THEM 742 00:26:03,141 --> 00:26:04,209 DEFECTIVE UNLESS ABLE TO 743 00:26:04,209 --> 00:26:05,543 REPLICATE. 744 00:26:05,543 --> 00:26:08,713 HEPATITIS D TAKES THIS PROTEIN, 745 00:26:08,713 --> 00:26:11,716 IT LAUGHS AT IT, AND IT USES TO 746 00:26:11,716 --> 00:26:15,420 MUTATE THAT A TO A G. 747 00:26:15,420 --> 00:26:19,858 THAT CODON 196 NOW BECOMES 748 00:26:19,858 --> 00:26:21,192 ATRYPTOPHAN, AND THE PROTEIN 749 00:26:21,192 --> 00:26:23,261 GETS EXTENDED 17 TO 19 AMINO 750 00:26:23,261 --> 00:26:24,996 ACIDS FURTHER, AND THAT 751 00:26:24,996 --> 00:26:26,531 EXTENSION, DEPENDING ON THE 752 00:26:26,531 --> 00:26:29,401 GENOTYPE 17 TO 19, NOW HAS A 753 00:26:29,401 --> 00:26:31,870 SITE THERE, WHICH IS A CXX 754 00:26:31,870 --> 00:26:36,942 MOTIF, WHICH. 755 00:26:36,942 --> 00:26:38,877 THAT'S INCREDIBLY IMPORTANT 756 00:26:38,877 --> 00:26:41,713 BECAUSE THAT MOTIF ALLOWS A 757 00:26:41,713 --> 00:26:42,514 JOURNAL-JOURNAL TRANSFERASE, A 758 00:26:42,514 --> 00:26:45,684 HOST PROTEIN, HOST ENZYME, TO 759 00:26:45,684 --> 00:26:47,319 THEN TAKE A PARENTAL GROUP, 760 00:26:47,319 --> 00:26:48,853 ATTACH TO THE PROTEIN, WHICH 761 00:26:48,853 --> 00:26:51,022 ALLOWS TO INSERT ITSELF INTO THE 762 00:26:51,022 --> 00:26:54,526 HEPATITIS B MEMBRANE. 763 00:26:54,526 --> 00:26:55,527 SO LET'S THINK ABOUT IT. 764 00:26:55,527 --> 00:26:56,928 IT TAKES A HOST PROTEIN WHICH 765 00:26:56,928 --> 00:27:00,799 SHOULD BE DEFENDING US AGAINST 766 00:27:00,799 --> 00:27:05,036 VIRUSES, IT THEN USES THAT TO 767 00:27:05,036 --> 00:27:06,771 GET RID OF A STOP CODON TO MAKE 768 00:27:06,771 --> 00:27:09,307 A LARGE ANTIGEN WHICH NOW 769 00:27:09,307 --> 00:27:12,143 INCLUDES A MOTIF WHICH ALLOWS TO 770 00:27:12,143 --> 00:27:13,578 INSERT INTO HEPATITIS B ENVELOPE 771 00:27:13,578 --> 00:27:16,748 WHICH IT LETS IT GET OUT OF THE 772 00:27:16,748 --> 00:27:17,515 CELL. 773 00:27:17,515 --> 00:27:22,887 IT'S DIABOLICAL. 774 00:27:22,887 --> 00:27:27,025 SO YOUR WE SO NOW WE HAVE AN IND 775 00:27:27,025 --> 00:27:27,459 HUMAN. 776 00:27:27,459 --> 00:27:28,793 WE YOU UNDERSTAND STAND THE 777 00:27:28,793 --> 00:27:30,395 LIFECYCLE, WE UNDERSTAND HOW THE 778 00:27:30,395 --> 00:27:31,830 VIRUS GET OUT AND TRANSMITTED TO 779 00:27:31,830 --> 00:27:32,497 THE NEXT PERSON. 780 00:27:32,497 --> 00:27:35,367 SO BEFORE I HAND OVER TO 781 00:27:35,367 --> 00:27:37,335 DR. KOTTILIL, LET'S SUMMARIZE. 782 00:27:37,335 --> 00:27:39,604 48 YEARS WE'RE STILL STRUGGLING. 783 00:27:39,604 --> 00:27:41,840 STRUGGLE IS REAL. 784 00:27:41,840 --> 00:27:43,008 BUT SLOWLY, SLOWLY. 785 00:27:43,008 --> 00:27:45,076 SO IT'S LIKE THE OLD JOKE, THE 786 00:27:45,076 --> 00:27:46,511 SON COMES HOME FROM SCHOOL, HIS 787 00:27:46,511 --> 00:27:47,379 MOTHER SAYS WHAT DID YOU LEARN 788 00:27:47,379 --> 00:27:48,146 TODAY? 789 00:27:48,146 --> 00:27:49,914 HE SAYS NOT ENOUGH. 790 00:27:49,914 --> 00:27:51,649 SHE SAYS WHY DO YOU SAY THAT? 791 00:27:51,649 --> 00:27:52,851 HE SAYS BECAUSE WE HAVE TO COME 792 00:27:52,851 --> 00:27:53,184 BACK TOMORROW. 793 00:27:53,184 --> 00:27:54,386 SO THE SAME THING HERE, WE HAVE 794 00:27:54,386 --> 00:27:55,353 TO KEEP GOING. 795 00:27:55,353 --> 00:27:57,455 HEPATITIS D IS FASCINATING. 796 00:27:57,455 --> 00:27:59,090 THE EPIDEMIOLOGY IS NOT ALWAYS 797 00:27:59,090 --> 00:28:00,392 PREDICTABLE, BUT IT'S SOMEWHAT 798 00:28:00,392 --> 00:28:00,692 UNDERSTOOD. 799 00:28:00,692 --> 00:28:03,828 WE HAVE LOW RESOLUTION IMAGES. 800 00:28:03,828 --> 00:28:06,798 DIAGNOSTIC ASSAYS ARE STILL 801 00:28:06,798 --> 00:28:08,066 LACKING BUT THE CLINICAL CENTER 802 00:28:08,066 --> 00:28:10,035 IS ABOUT TO BE INVOLVED IN A 803 00:28:10,035 --> 00:28:11,836 STUDY WITH ROCHE TO DEVELOP AN 804 00:28:11,836 --> 00:28:15,774 ASSAY TO LICENSE THEIR ASSAY FOR 805 00:28:15,774 --> 00:28:17,909 NORTH AMERICA, WHICH WILL DETECT 806 00:28:17,909 --> 00:28:19,277 GENOTYPES 1 THROUGH 8. 807 00:28:19,277 --> 00:28:20,412 BIOLOGY IS INCREDIBLE. 808 00:28:20,412 --> 00:28:25,650 THE WHOLE THING, RIBOZYMES, 809 00:28:25,650 --> 00:28:27,118 MOTIFS, THINK ABOUT IT AS A 810 00:28:27,118 --> 00:28:28,219 MODEL FOR CLINICIANS. 811 00:28:28,219 --> 00:28:31,089 HERE YOU HAVE A DISEASE WHERE 812 00:28:31,089 --> 00:28:33,525 RAPIDLY AND REPRODUCIBLY 70 TO 813 00:28:33,525 --> 00:28:35,360 90% WILL DEVELOP FIBROSIS IN 10 814 00:28:35,360 --> 00:28:35,627 YEARS. 815 00:28:35,627 --> 00:28:37,395 IMAGINE IF YOU WANT TO 816 00:28:37,395 --> 00:28:39,130 UNDERSTAND FIBROSIS DEVELOPMENT. 817 00:28:39,130 --> 00:28:43,935 AND FASCINATING THIS THAT IT GP 818 00:28:43,935 --> 00:28:45,703 EVERYTHING AND SHRUNK DOWN TO 819 00:28:45,703 --> 00:28:46,805 ALMOST EXCLUSIVELY IN HOST 820 00:28:46,805 --> 00:28:47,238 REPLICATION. 821 00:28:47,238 --> 00:28:48,540 WHAT YOU'RE ABOUT TO HEAR IN THE 822 00:28:48,540 --> 00:28:50,075 NEXT SECTION OF THE TALK IS A 823 00:28:50,075 --> 00:28:51,609 REVOLUTION IN SCIENCE-BASED 824 00:28:51,609 --> 00:28:53,344 THERAPEUTICS. 825 00:28:53,344 --> 00:28:54,879 I WANT TO THANK THE PATIENTS, 826 00:28:54,879 --> 00:28:57,949 NURSES, FELLOWS, COLLABORATORS, 827 00:28:57,949 --> 00:28:58,950 DR. CHRISTOPHER IS ABOUT TO DO 828 00:28:58,950 --> 00:29:02,554 SOME REEL REALLY INNOVATIVE 829 00:29:02,554 --> 00:29:03,655 THERAPEUTIC STUDIES HERE AT THE 830 00:29:03,655 --> 00:29:04,956 CLINICAL CENTER, THE PATHOLOGIST 831 00:29:04,956 --> 00:29:06,458 WE WORK WITH WHO MAKES 832 00:29:06,458 --> 00:29:07,792 EVERYTHING POSSIBLE, 833 00:29:07,792 --> 00:29:10,628 DR. KLEINER, DR. LIANG, THE MOST 834 00:29:10,628 --> 00:29:11,629 INCREDIBLE LIVER DISEASE BRANCH 835 00:29:11,629 --> 00:29:13,364 WHERE ALL OF THIS WORK HAPPENS, 836 00:29:13,364 --> 00:29:14,999 HE'S CREATING AN ENVIRONMENT 837 00:29:14,999 --> 00:29:16,768 WHERE GROWTH AND INNOVATION IS 838 00:29:16,768 --> 00:29:20,605 POSSIBLE, AND DR. HOOFNAGLE, WHO 839 00:29:20,605 --> 00:29:21,906 DID SOME OF THE VERY FIRST 840 00:29:21,906 --> 00:29:23,675 INTERFERON STUDIES EVER WITH 841 00:29:23,675 --> 00:29:24,142 HEPATITIS D. 842 00:29:24,142 --> 00:29:24,943 AND THAT'S A PICTURE OF THE 843 00:29:24,943 --> 00:29:26,811 GROUP WITH DR. LIANG IN THE 844 00:29:26,811 --> 00:29:31,082 CENTER. 845 00:29:31,082 --> 00:29:32,283 DR. HOOFNAGLE NEXT TO HIM AND 846 00:29:32,283 --> 00:29:32,951 DR. KLEINER ON THE OTHER SIDE. 847 00:29:32,951 --> 00:29:34,586 I JUST WANT TO REMIND YOU, FROM 848 00:29:34,586 --> 00:29:36,121 PANEL A TO PANEL D, THAT'S WHAT 849 00:29:36,121 --> 00:29:36,921 WE'RE AIMING FOR. 850 00:29:36,921 --> 00:29:39,057 WE DON'T WANT CIRRHOSIS, WE WANT 851 00:29:39,057 --> 00:29:40,692 TO ELIMINATE CIRRHOSIS, WE WANT 852 00:29:40,692 --> 00:29:41,926 TO ELIMINATE DEATH, WE WANT TO 853 00:29:41,926 --> 00:29:43,561 ELIMINATE THE VIRUS, AND WE WANT 854 00:29:43,561 --> 00:29:45,430 EVERYONE'S LIVER TO BE THE 855 00:29:45,430 --> 00:29:46,331 NORMAL. 856 00:29:46,331 --> 00:29:48,600 MAYA ANGELOU SAID IT BEST, LIFE 857 00:29:48,600 --> 00:29:49,934 LOVES THE LIVER OF IT. 858 00:29:49,934 --> 00:29:50,268 THANK YOU. 859 00:29:50,268 --> 00:30:00,445 [APPLAUSE] 860 00:30:12,190 --> 00:30:14,392 >> THANK YOU FOR THAT 861 00:30:14,392 --> 00:30:14,759 INTRODUCTION. 862 00:30:14,759 --> 00:30:16,261 IT'S A GREAT HONOR TO GIVE THIS 863 00:30:16,261 --> 00:30:18,663 TALK WITH THEOHELLER, WHO'S 864 00:30:18,663 --> 00:30:20,198 DEDICATED A LOT OF TIME IN 865 00:30:20,198 --> 00:30:21,299 STUDYING HEPATITIS DELTA FOR 866 00:30:21,299 --> 00:30:23,168 MANY YEARS. 867 00:30:23,168 --> 00:30:24,302 MUCH HE KNOWS DELTA INSIDE AND 868 00:30:24,302 --> 00:30:25,236 OUT MORE THAN I DO. 869 00:30:25,236 --> 00:30:29,073 I'LL TRY TO SUMMARIZE SOME OF 870 00:30:29,073 --> 00:30:30,775 THE ASPECTS OF IT THAT LOOK TO 871 00:30:30,775 --> 00:30:32,043 THE NEW PROMISING THERAPEUTICS 872 00:30:32,043 --> 00:30:34,445 THAT HAS COME UP IN HEPATITIS 873 00:30:34,445 --> 00:30:34,879 DELTA. 874 00:30:34,879 --> 00:30:36,281 THESE ARE MY DISCLOSURES. 875 00:30:36,281 --> 00:30:37,615 NOTHING BIG DEAL RELATED TO THE 876 00:30:37,615 --> 00:30:37,949 PRESENTATION. 877 00:30:37,949 --> 00:30:40,118 I WILL BE DISCUSSING MOST OF THE 878 00:30:40,118 --> 00:30:43,354 STUFF WHICH IS NOT FDA-APPROVED. 879 00:30:43,354 --> 00:30:45,323 THE OBJECTIVE IS TO JUST 880 00:30:45,323 --> 00:30:46,624 UNDERSTAND THAT AGNOSTIC 881 00:30:46,624 --> 00:30:48,459 CRITERIA, SOME OF WHICH WAS JUST 882 00:30:48,459 --> 00:30:49,561 COVERED, AND THERAPEUTIC 883 00:30:49,561 --> 00:30:51,763 PIPELINE AND ALSO THE CORRELATES 884 00:30:51,763 --> 00:30:52,964 IN IMMUNE AND CLINICAL END 885 00:30:52,964 --> 00:30:54,566 POINTS THAT GUIDE THERAPEUTIC 886 00:30:54,566 --> 00:30:56,034 RESPONSE FOR HEPATITIS DELTA. 887 00:30:56,034 --> 00:31:00,138 AS DR. HELLER MENTIONED, 888 00:31:00,138 --> 00:31:02,173 HEPATITIS DELTA IS AN ENANYTHING 889 00:31:02,173 --> 00:31:04,242 MA, THERE ARE POCKETS OF 890 00:31:04,242 --> 00:31:05,376 INFECTION REPORTED HIGH IN 891 00:31:05,376 --> 00:31:08,079 PLACES LIKE MONGOLIA, PAKISTAN 892 00:31:08,079 --> 00:31:09,714 AND TURKEY, BUT MANY OF THESE 893 00:31:09,714 --> 00:31:11,249 THINGS ARE VERY SMALL STUDIES 894 00:31:11,249 --> 00:31:12,917 AND THE REAL PREVALENCE OF DELTA 895 00:31:12,917 --> 00:31:14,452 IS NOT REALLY UNDERSTOOD. 896 00:31:14,452 --> 00:31:15,420 MOST OF THE GUIDANCE AND 897 00:31:15,420 --> 00:31:16,287 SCREENING IS STILL BASED ON 898 00:31:16,287 --> 00:31:19,457 WHERE YOU ARE FROM RATHER THAN 899 00:31:19,457 --> 00:31:22,427 FROM CHARACTERISTICS. 900 00:31:22,427 --> 00:31:24,696 THERE WAS A CLASSIC STUDY IN THE 901 00:31:24,696 --> 00:31:27,565 80s IN HIV, YOU DO HIV 902 00:31:27,565 --> 00:31:28,700 SEROLOGY TESTING IN PEOPLE AT 903 00:31:28,700 --> 00:31:33,571 HIGH RISK FOR HIV, YOU HAVE 904 00:31:33,571 --> 00:31:36,808 SCREENING SENSE AT SENSITIVITYF 905 00:31:36,808 --> 00:31:41,045 PEOPLE WHO INJECT DRUGS, 100% 906 00:31:41,045 --> 00:31:41,446 PREDICTIVE VALUE. 907 00:31:41,446 --> 00:31:43,314 YOU TAKE THE SAME TEST AND GO TO 908 00:31:43,314 --> 00:31:45,183 MIDWEST AND TEST KINDERGARTEN 909 00:31:45,183 --> 00:31:47,252 TEACHERS, YOU SEE THE 910 00:31:47,252 --> 00:31:48,253 SENSITIVITY POSITIVITY VALUE 911 00:31:48,253 --> 00:31:49,087 DROPS TO 50%. 912 00:31:49,087 --> 00:31:49,887 SAME IS TRUE HERE. 913 00:31:49,887 --> 00:31:53,391 ANY TEST YOU HAVE, THE 914 00:31:53,391 --> 00:31:54,692 PREVALENCE DETERMINES THE 915 00:31:54,692 --> 00:31:55,560 POSITIVITY VL EU. 916 00:31:55,560 --> 00:31:57,262 IF YOU LOOK AT -- SCREENING, YOU 917 00:31:57,262 --> 00:31:58,463 HAVE TO SCREEN A LOT OF PEOPLE 918 00:31:58,463 --> 00:32:00,064 WHO ARE INFECTED BUT IF YOU LOOK 919 00:32:00,064 --> 00:32:01,065 TO PEOPLE WHO ARE SPECIFICALLY 920 00:32:01,065 --> 00:32:02,667 FOCUSED WITH LIVER DISEASE AS 921 00:32:02,667 --> 00:32:04,102 WAS MENTIONED BY DR. HELLER, YOU 922 00:32:04,102 --> 00:32:05,737 ARE LIKELY TO FIND MORE 923 00:32:05,737 --> 00:32:07,171 HEPATITIS DELTA. 924 00:32:07,171 --> 00:32:09,240 IT WAS MENTIONED BEFORE THAT WHO 925 00:32:09,240 --> 00:32:11,442 GETS DELTA, I WANT TO QUICKLY 926 00:32:11,442 --> 00:32:12,744 GO -- THERE ARE TWO WAYS YOU GET 927 00:32:12,744 --> 00:32:14,379 IT, EITHER COINFECTION, WHERE 928 00:32:14,379 --> 00:32:16,114 YOU GET BOTH B AND C TOGETHER, 929 00:32:16,114 --> 00:32:17,882 OR YOU SOMETIMES CAN GET A 930 00:32:17,882 --> 00:32:19,317 CHRONIC HEPATITIS B ON TOP OF 931 00:32:19,317 --> 00:32:20,618 THAT, YOU GET THE SECOND 932 00:32:20,618 --> 00:32:22,253 EXPOSURE AND YOU GET A CHRONIC 933 00:32:22,253 --> 00:32:23,154 DELTA INFECTION ESTABLISHED. 934 00:32:23,154 --> 00:32:25,023 THIS -- THE FIRST ONE IS 935 00:32:25,023 --> 00:32:27,058 IMPORTANT, THE ONLY ONE REALLY 936 00:32:27,058 --> 00:32:28,159 GOOD STRATEGY THAT WE HAVE TODAY 937 00:32:28,159 --> 00:32:30,595 IS TO PREVENT HEPATITIS B. 938 00:32:30,595 --> 00:32:31,729 SO IF YOU DON'T HAVE HEPATITIS 939 00:32:31,729 --> 00:32:34,632 B, YOU WON'T GET HEPATITIS 940 00:32:34,632 --> 00:32:35,533 DELTA. 941 00:32:35,533 --> 00:32:36,968 EARLIER COINFECTION IS 942 00:32:36,968 --> 00:32:37,835 COMPLETELY -- OF VACCINES AND 943 00:32:37,835 --> 00:32:39,237 MANY OF THESE PLACES THE VACCINE 944 00:32:39,237 --> 00:32:41,005 UP TAKE FOR HEPATITIS B WAS NOT 945 00:32:41,005 --> 00:32:42,106 GREAT UNTIL RECENTLY, SO THAT'S 946 00:32:42,106 --> 00:32:43,641 ONE OF THE REASONS WHY YOU HAVE 947 00:32:43,641 --> 00:32:46,244 COINFECTIONS WITH DELTA AT ALL. 948 00:32:46,244 --> 00:32:49,314 THE SECOND SCENARIO IS IF YOU 949 00:32:49,314 --> 00:32:50,181 HAVE COINFECTION BECAUSE OF 950 00:32:50,181 --> 00:32:51,082 CONTINUED RISK FACTOR THAT 951 00:32:51,082 --> 00:32:54,452 PEOPLE MAY HAVE. 952 00:32:54,452 --> 00:32:56,521 YOU HAVE A PATIENT WHO IS 953 00:32:56,521 --> 00:32:59,590 ACUTELY DISEASE -- SO THE FIRST 954 00:32:59,590 --> 00:33:00,258 ALGORITHM IS THAT YOU HAVE 955 00:33:00,258 --> 00:33:01,659 SOMEONE COME IN, YOU SCREEN FOR 956 00:33:01,659 --> 00:33:05,730 HEPATITIS VIRUSES, AND IF THEY 957 00:33:05,730 --> 00:33:07,665 TURN OUT HEPATITIS B POSITIVE, 958 00:33:07,665 --> 00:33:10,401 THEN YOU LOOK FOR ACUTE OR 959 00:33:10,401 --> 00:33:13,805 HEPATITIS B. 960 00:33:13,805 --> 00:33:15,907 -- TEST FOR HDV WITH RNA. 961 00:33:15,907 --> 00:33:17,408 IF THEY ARE RNA POSITIVE THEY 962 00:33:17,408 --> 00:33:18,876 HAVE DELTA AND RNA NEGATIVE, 963 00:33:18,876 --> 00:33:20,244 THEY DON'T. 964 00:33:20,244 --> 00:33:22,680 BUT IF YOU HAVE -- YOU DO NOT 965 00:33:22,680 --> 00:33:24,515 HAVE A -- FOR HEPATITIS B THEN 966 00:33:24,515 --> 00:33:26,484 YOU HAVE CHRONIC HEPATITIS B. 967 00:33:26,484 --> 00:33:27,919 SO THEN YOU STILL GO TO THE 968 00:33:27,919 --> 00:33:29,454 RIGHT SIDE OF THE ALGORITHM, 969 00:33:29,454 --> 00:33:33,591 WHERE YOU TEST FOR IMMUNOIGM FOR 970 00:33:33,591 --> 00:33:34,025 HEPATITIS DELTA. 971 00:33:34,025 --> 00:33:36,461 IF SEROLOGY IS POSITIVE THEN YOU 972 00:33:36,461 --> 00:33:38,396 LOOK FOR RNA. 973 00:33:38,396 --> 00:33:40,698 SEROLOGY IS POSITIVE AND IF RNA 974 00:33:40,698 --> 00:33:42,300 IS NEGATIVE, THEY HAVE RESOLVED 975 00:33:42,300 --> 00:33:43,334 INFECTION AND IF THE RNA IS 976 00:33:43,334 --> 00:33:44,769 POSITIVE YOU HAVE A CHRONIC 977 00:33:44,769 --> 00:33:45,636 HEPATITIS DELTA. 978 00:33:45,636 --> 00:33:46,938 SO THAT'S THE USUAL ALGORITHM. 979 00:33:46,938 --> 00:33:48,473 WHO SHOULD BE TESTED? 980 00:33:48,473 --> 00:33:49,807 DR. HELLER POINTED OUT THIS IS 981 00:33:49,807 --> 00:33:51,209 VERY DIFFICULT AFTER TIME, IT IS 982 00:33:51,209 --> 00:33:52,510 NOT REALLY UNDERTAKEN. 983 00:33:52,510 --> 00:33:55,813 THETHE GUIDELINES ARE VERY 984 00:33:55,813 --> 00:33:56,114 RESTRICTIVE. 985 00:33:56,114 --> 00:33:57,148 SOME PEOPLE SAY EVERYBODY SHOULD 986 00:33:57,148 --> 00:33:58,950 BE TESTED, BUT WE ACTUALLY DO 987 00:33:58,950 --> 00:34:01,085 NOT DO THAT IN REGULAR PRACTICE. 988 00:34:01,085 --> 00:34:02,920 I JUST WANT TO GO OVER THE 989 00:34:02,920 --> 00:34:03,788 UNIVERSAL TESTING IS VERY 990 00:34:03,788 --> 00:34:04,789 DIFFICULT BECAUSE WE DON'T 991 00:34:04,789 --> 00:34:06,090 REALLY HAVE GOOD ASSAYS AND 992 00:34:06,090 --> 00:34:07,558 THAT'S ONE OF THE BIG PROBLEMS 993 00:34:07,558 --> 00:34:10,395 OF DEVELOPING POSITIVE, FALSE 994 00:34:10,395 --> 00:34:11,129 POSITIVE, FALSE NEGATIVE. 995 00:34:11,129 --> 00:34:14,298 WE DON'T REALLY HAVE AN 996 00:34:14,298 --> 00:34:15,633 FDA-APPROVED PCR FOR DELTA WHICH 997 00:34:15,633 --> 00:34:17,468 IS THE BACK BOAP OF TREATMENT 998 00:34:17,468 --> 00:34:19,237 RESPONSE AND THAT'S WHAT 999 00:34:19,237 --> 00:34:20,204 DR. HELLER MENTIONED THAT ROCHE 1000 00:34:20,204 --> 00:34:21,205 IS LOOKING INTO DEVELOPING SUCH 1001 00:34:21,205 --> 00:34:22,073 A PLATFORM ASSAY. 1002 00:34:22,073 --> 00:34:24,942 I WILL JUST GO THROUGH THE -- 1003 00:34:24,942 --> 00:34:26,711 MANY TESTING THAT WORKED FOR 1004 00:34:26,711 --> 00:34:29,213 HEPATITIS B AND HEPATITIS C 1005 00:34:29,213 --> 00:34:30,515 REFLECTS UNIVERSAL TESTING -- 1006 00:34:30,515 --> 00:34:31,716 DOESN'T REALLY PAN OUT HERE 1007 00:34:31,716 --> 00:34:33,017 BECAUSE YOU'D HAVE TO TEST A LOT 1008 00:34:33,017 --> 00:34:34,352 OF PEOPLE TO FIND DELTA. 1009 00:34:34,352 --> 00:34:36,320 THE LAST LINE IS WHAT I READ 1010 00:34:36,320 --> 00:34:37,622 THAT UNIVERSAL SCREENING IS 1011 00:34:37,622 --> 00:34:38,523 COST-EFFECTIVE IF YOU HAVE LOW 1012 00:34:38,523 --> 00:34:41,025 PREVALENCE OF HEPATITIS B AND 1013 00:34:41,025 --> 00:34:42,260 HIGH PREVALENCE OF DELTA. 1014 00:34:42,260 --> 00:34:43,561 IT'S NOT GOING TO BE 1015 00:34:43,561 --> 00:34:44,362 COST-EFFECTIVE IF YOU HAVE VERY 1016 00:34:44,362 --> 00:34:46,397 HIGH PROBLEMS WITH HBV AND 1017 00:34:46,397 --> 00:34:47,932 REALLY LOW PROBLEMS OF DELTA 1018 00:34:47,932 --> 00:34:48,232 COINFECTION. 1019 00:34:48,232 --> 00:34:50,334 WE NEED TO KNOW THAT THE 1020 00:34:50,334 --> 00:34:52,336 PREVENTIVE VACCINE IS -- 1021 00:34:52,336 --> 00:34:57,141 HEPATITIS B IS AVAILABLE, AND 1022 00:34:57,141 --> 00:34:58,910 THAT'S UPTAKE OF THE VACCINE 1023 00:34:58,910 --> 00:35:00,878 WILL HELP CONTROL CHRONIC 1024 00:35:00,878 --> 00:35:03,915 HEPATITIS B AS DELTA. 1025 00:35:03,915 --> 00:35:05,349 THE TREATMENT, THERE'S NO 1026 00:35:05,349 --> 00:35:07,018 FDA-APPROVED TREATMENT, BUT THE 1027 00:35:07,018 --> 00:35:08,953 TREATMENT THAT MOST PEOPLE USE 1028 00:35:08,953 --> 00:35:15,326 IS INTERFERON ALPHA. 1029 00:35:15,326 --> 00:35:18,262 -- FOR US TO FIND OUT THAT THE 1030 00:35:18,262 --> 00:35:20,565 LIVER ISN'T DAMAGED AND YOU 1031 00:35:20,565 --> 00:35:22,533 DON'T HAVE CARCINOMA. 1032 00:35:22,533 --> 00:35:23,868 HAVING DELTA COINFECTION WILL 1033 00:35:23,868 --> 00:35:27,572 INCREASE THE CHANCES OF GETTING 1034 00:35:27,572 --> 00:35:30,074 INFECTION, MULTIPLE FOLD AND 1035 00:35:30,074 --> 00:35:32,710 DEVELOP CIRRHOSIS, SO THIS IS 1036 00:35:32,710 --> 00:35:33,911 WHAT HAPPENS AND THE CONCEPT IS 1037 00:35:33,911 --> 00:35:36,614 THAT YOU HAVE AP ANTIVIRAL 1038 00:35:36,614 --> 00:35:37,982 TREATMENT THAT CAN SLOW THIS 1039 00:35:37,982 --> 00:35:38,749 PROCESS DOWN. 1040 00:35:38,749 --> 00:35:40,084 REALLY WE DON'T HAVE 1041 00:35:40,084 --> 00:35:41,586 THERAPEUTICS OR FUNCTIONAL CURE 1042 00:35:41,586 --> 00:35:42,820 FOR HEPATITIS DELTA YET BUT AT 1043 00:35:42,820 --> 00:35:44,188 LEAST THE THERAPEUTICS WILL 1044 00:35:44,188 --> 00:35:46,123 OFFER YOU SOME SLOWING OF THE 1045 00:35:46,123 --> 00:35:47,859 PROCESS. 1046 00:35:47,859 --> 00:35:50,361 DR. HELLER MENTIONED SEVERAL 1047 00:35:50,361 --> 00:35:50,928 THERAPEUTICS ARE BEING 1048 00:35:50,928 --> 00:35:51,262 DEVELOPED. 1049 00:35:51,262 --> 00:35:53,798 THIS IS A REALLY CONCISE WAY OF 1050 00:35:53,798 --> 00:35:57,668 LOOKING AT ONE OF THE ENTRY 1051 00:35:57,668 --> 00:35:57,969 INHIBITOR. 1052 00:35:57,969 --> 00:36:00,271 THERE ARE AGENTS LIKE INTERFERON 1053 00:36:00,271 --> 00:36:02,139 TO BLOCK DIFFERENT ASPECTS OF 1054 00:36:02,139 --> 00:36:06,377 HDV REPLICATION, AND YOU HAVE 1055 00:36:06,377 --> 00:36:09,113 RNA AGENTS -- SO THEY CAN BLOCK 1056 00:36:09,113 --> 00:36:09,780 DELTA TRANSCRIPTION AND 1057 00:36:09,780 --> 00:36:12,283 INTERRUPT THE LIFECYCLE. 1058 00:36:12,283 --> 00:36:14,819 THE GREAT -- WHICH I'LL GET INTO 1059 00:36:14,819 --> 00:36:16,721 IT IS AN INHIBITOR THAT HAS BEEN 1060 00:36:16,721 --> 00:36:19,857 USED AN ALSO THIS NUCLEIC ACID 1061 00:36:19,857 --> 00:36:23,828 POLYMER THAT IS ALSO -- 1062 00:36:23,828 --> 00:36:24,695 ANTIVIRAL ACTIVITY. 1063 00:36:24,695 --> 00:36:26,230 THERE ARE AGENTS THAT MAY WORK 1064 00:36:26,230 --> 00:36:28,833 IN BOOSTING IMMUNE RESPONSE, 1065 00:36:28,833 --> 00:36:30,935 VERY EARLY CLINICAL STAGES ARE 1066 00:36:30,935 --> 00:36:33,905 IN CONCEPT, NOT DEVELOPED YET. 1067 00:36:33,905 --> 00:36:35,773 CLINICAL END POINTS FOR -- 1068 00:36:35,773 --> 00:36:36,507 DELTA. 1069 00:36:36,507 --> 00:36:38,376 USUALLY CAN YOU DO FINITE 1070 00:36:38,376 --> 00:36:39,911 TREATMENT PARADIGMS OR YOU CAN 1071 00:36:39,911 --> 00:36:41,112 ACTUALLY USE MAINTENANCE LONG 1072 00:36:41,112 --> 00:36:41,746 TERM TREATMENT RESPONSE. 1073 00:36:41,746 --> 00:36:45,116 I SHOW YOU BOTH DATA -- RESPONSE 1074 00:36:45,116 --> 00:36:46,250 TIME IS YOU CAN TREAT FOR SOME 1075 00:36:46,250 --> 00:36:47,985 TIME AND THEN STOP TREATMENT AND 1076 00:36:47,985 --> 00:36:52,590 SEE WHETHER WE ACTUALLY HAVE 1077 00:36:52,590 --> 00:36:54,258 LED -- BELOW THE LEVEL OF 1078 00:36:54,258 --> 00:36:55,560 DETECTION. 1079 00:36:55,560 --> 00:36:57,094 THE CLASSIC EXAMPLE, THEY DID 1080 00:36:57,094 --> 00:36:59,964 THE STUDY OF 41 PATIENTS WITH 1081 00:36:59,964 --> 00:37:01,365 HEP C, TREATED THEM AT SIX 1082 00:37:01,365 --> 00:37:02,733 MONTHS WITH INTERFERON THEN 1083 00:37:02,733 --> 00:37:03,434 STOPPED TREATMENT. 1084 00:37:03,434 --> 00:37:06,537 SIX MONTHS LATER, WE FOUND THAT 1085 00:37:06,537 --> 00:37:08,072 PERCENTAGE OF PEOPLE ACTUALLY 1086 00:37:08,072 --> 00:37:10,308 HAD NO DETECTABLE HEPATITIS C 1087 00:37:10,308 --> 00:37:11,475 THAT WAS REALLY LANDMARK TO BE 1088 00:37:11,475 --> 00:37:13,444 ABLE TO SAY THAT HEPATITIS C CAN 1089 00:37:13,444 --> 00:37:15,313 ACHIEVE A FUNCTIONAL CURE. 1090 00:37:15,313 --> 00:37:16,514 AND THAT'S THE KEET STEP FOR 1091 00:37:16,514 --> 00:37:17,081 THAT. 1092 00:37:17,081 --> 00:37:19,817 SO THAT'S A VERY -- SOME STUDIES 1093 00:37:19,817 --> 00:37:21,452 HAVE LOOKED AT FINITE TREATMENT. 1094 00:37:21,452 --> 00:37:22,887 THE MAJORITY OF NEWER STUDIES 1095 00:37:22,887 --> 00:37:24,956 HAVE LOOKED AT MAINTENANCE 1096 00:37:24,956 --> 00:37:25,923 TREATMENT, BECAUSE THEY DON'T 1097 00:37:25,923 --> 00:37:27,291 THINK THE FUNCTIONAL TREATMENT 1098 00:37:27,291 --> 00:37:29,460 IS ACHIEVABLE WITH THE 1099 00:37:29,460 --> 00:37:30,761 CURRENT -- AT THIS TIME SO MOST 1100 00:37:30,761 --> 00:37:32,730 OF THESE ARE LOOKING AT WHETHER 1101 00:37:32,730 --> 00:37:37,868 THERE'S A DECLINE THAT LEADS 1102 00:37:37,868 --> 00:37:40,171 TO -- IF THERE'S NORMAL ALT 1103 00:37:40,171 --> 00:37:43,941 THERE IS LESS INFLAMMATION. 1104 00:37:43,941 --> 00:37:45,142 SO THE COMBINED RESPONSE IS WHAT 1105 00:37:45,142 --> 00:37:47,278 I WOULD REFER TO MOST PART AND 1106 00:37:47,278 --> 00:37:48,980 IT'S SOMETHING THAT MOST OF THE 1107 00:37:48,980 --> 00:37:50,514 DRUG STUDIES HAVE BEEN DONE THAT 1108 00:37:50,514 --> 00:37:53,484 HAVE LED TO THIS PART. 1109 00:37:53,484 --> 00:37:54,452 INTERFERON IS DEFINITELY USED, 1110 00:37:54,452 --> 00:37:55,586 I'M NOT GOING TO SPEND A LOT OF 1111 00:37:55,586 --> 00:37:56,253 TIME. 1112 00:37:56,253 --> 00:37:57,888 THE REASON IS THAT HEPATITIS 1113 00:37:57,888 --> 00:38:01,292 DELTA, EVERYBODY KNEW DELTA -- 1114 00:38:01,292 --> 00:38:05,129 COINFECTION WILL LEAD TO RAPID 1115 00:38:05,129 --> 00:38:06,964 DEVELOPMENT OF FIBROSIS AND WE 1116 00:38:06,964 --> 00:38:08,032 HAD TO TREAT THESE PEOPLE AND 1117 00:38:08,032 --> 00:38:09,500 THERE WAS NOTHING AVAILABLE SO 1118 00:38:09,500 --> 00:38:12,236 MANY OF THESE STUDIES, PATIENT 1119 00:38:12,236 --> 00:38:14,639 ARE TREATED WITH INTERFERON 1120 00:38:14,639 --> 00:38:15,406 ALPHA. 1121 00:38:15,406 --> 00:38:17,308 IT DEFINITELY HAS SOME SUCCESS. 1122 00:38:17,308 --> 00:38:18,509 INTERFERON STUDIES WERE DONE AS 1123 00:38:18,509 --> 00:38:19,710 FINITE STUDIES, AND THIS HAS 1124 00:38:19,710 --> 00:38:20,778 BEEN DONE MANY YEARS AGO. 1125 00:38:20,778 --> 00:38:23,648 YOU HAVE REALLY HAD GOOD DATA ON 1126 00:38:23,648 --> 00:38:28,252 THE LONG TERM CON QENSES ON WHAT 1127 00:38:28,252 --> 00:38:29,020 HAPPENS -- DECOMPENSATION, ET 1128 00:38:29,020 --> 00:38:30,121 CETERA, LATER ON WHICH DOESN'T 1129 00:38:30,121 --> 00:38:33,190 EXIST FOR THE NEWER TREATMENT. 1130 00:38:33,190 --> 00:38:34,392 SO -- EVEN THOUGH IT DOESN'T 1131 00:38:34,392 --> 00:38:36,060 REALLY TRANSLATE INTO SUCCESS OF 1132 00:38:36,060 --> 00:38:37,261 CURING A LOT OF PEOPLE, IT STILL 1133 00:38:37,261 --> 00:38:39,130 HAS BEEN SUCCESSFULLY SHOWN THAT 1134 00:38:39,130 --> 00:38:43,934 IT DOES HAVE REALLY GOOD 1135 00:38:43,934 --> 00:38:45,603 RESPONSE, GOOD THERAPEUTIC 1136 00:38:45,603 --> 00:38:47,138 OPTION FOR PEOPLE WITH CHRONIC 1137 00:38:47,138 --> 00:38:47,872 HEPATITIS B. 1138 00:38:47,872 --> 00:38:54,078 THE FIRST ONE I GO TO, FIRST 1139 00:38:54,078 --> 00:38:58,416 DEVELOPED -- VERY SIMILAR TO 1140 00:38:58,416 --> 00:39:02,119 IMMUNO -- VERY SIMILAR -- THAT 1141 00:39:02,119 --> 00:39:04,955 WILL CONTINUALLY BLOCK -- AND 1142 00:39:04,955 --> 00:39:05,389 BLOCK ENTRY. 1143 00:39:05,389 --> 00:39:06,657 IT WAS INITIALLY DEVELOPED FOR 1144 00:39:06,657 --> 00:39:08,059 TREATMENT FOR HEPATITIS B, 1145 00:39:08,059 --> 00:39:09,994 TURNED OUT THAT HEPATITIS B 1146 00:39:09,994 --> 00:39:11,562 SURFACE -- WAS NOT AFFECTED WHEN 1147 00:39:11,562 --> 00:39:13,431 YOU GIVE -- BUT IT DID HAVE AN 1148 00:39:13,431 --> 00:39:14,965 EFFECT ON HDV. 1149 00:39:14,965 --> 00:39:18,703 SO THEN IT WAS PROPOSED AS 1150 00:39:18,703 --> 00:39:20,738 THERAPEUTIC. 1151 00:39:20,738 --> 00:39:21,872 IT'S A DAILY INJECTION AND THIS 1152 00:39:21,872 --> 00:39:23,941 IS THE ONLY DRUG THAT IS 1153 00:39:23,941 --> 00:39:25,142 APPROVED IN THE EUROPEAN UNION. 1154 00:39:25,142 --> 00:39:26,677 IT'S NOT APPROVED IN THE UNITED 1155 00:39:26,677 --> 00:39:30,081 STATES, IT IS APPROVED FOR 1156 00:39:30,081 --> 00:39:31,949 TREATMENT FOR HEPATITIS DELTA. 1157 00:39:31,949 --> 00:39:33,150 SO VIROLOGICAL RESPONSE, YOU SEE 1158 00:39:33,150 --> 00:39:39,156 THE DECLINE IN VIRAL LOAD, 1159 00:39:39,156 --> 00:39:40,725 COMPARED TO PLACEBO. 1160 00:39:40,725 --> 00:39:41,792 CLINICAL RESPONSE, NORMALIZATION 1161 00:39:41,792 --> 00:39:45,062 OF ALT, IN NEW ENGLAND JOURNAL 1162 00:39:45,062 --> 00:39:46,197 OF MEDICINE A COUPLE YEARS AGO 1163 00:39:46,197 --> 00:39:47,732 SHOWED THERE IS A COMBINED 1164 00:39:47,732 --> 00:39:48,399 RESPONSE, ABOUT HALF OF THE 1165 00:39:48,399 --> 00:39:49,700 PEOPLE WILL HAVE NORMALIZATION 1166 00:39:49,700 --> 00:39:54,505 OF ALT, AND END OF TREATMENT AT 1167 00:39:54,505 --> 00:39:56,407 48 WHILE THEY'RE RECEIVING THE 1168 00:39:56,407 --> 00:39:56,674 TREATMENT. 1169 00:39:56,674 --> 00:40:00,010 THE COMBINATION RESPONSE 1170 00:40:00,010 --> 00:40:00,811 TREATMENT, SUBSEQUENTLY THIS HAS 1171 00:40:00,811 --> 00:40:02,913 BEEN USED EXTENSIVELY IN EUROPE. 1172 00:40:02,913 --> 00:40:05,416 AND EUROPE HAS -- IT'S APPROVED 1173 00:40:05,416 --> 00:40:06,684 THERE AND PEOPLE HAVE BEEN 1174 00:40:06,684 --> 00:40:08,686 TREATING THIS IN EUROPE. 1175 00:40:08,686 --> 00:40:10,454 THIS IS A GOOD SUMMARY OF THE 1176 00:40:10,454 --> 00:40:11,756 DATA THAT'S HAPPENING AFTER ALL 1177 00:40:11,756 --> 00:40:13,424 LATER ON WITH THE PATIENTS 1178 00:40:13,424 --> 00:40:14,158 TREATED WITH THIS. 1179 00:40:14,158 --> 00:40:15,392 SO THREE DIFFERENT RESPONSES 1180 00:40:15,392 --> 00:40:16,560 HERE, IT A CROWDED SLIDE. 1181 00:40:16,560 --> 00:40:18,429 THE BLUE ONE IS THE PEOPLE WHO 1182 00:40:18,429 --> 00:40:21,065 HAVE LEVELS OF HDV RNA BELOW THE 1183 00:40:21,065 --> 00:40:23,701 LEVEL OF DETECTION. 1184 00:40:23,701 --> 00:40:24,301 LOOKING AT THE RED LINE IS THE 1185 00:40:24,301 --> 00:40:26,437 PEOPLE WITH HDV RNA MORE THAN 1186 00:40:26,437 --> 00:40:27,104 TWO LOG DROP. 1187 00:40:27,104 --> 00:40:28,973 AND THE GREEN ONE IS A COMBINED 1188 00:40:28,973 --> 00:40:32,143 RESPONSE THAT MEANS THEY HAVE A 1189 00:40:32,143 --> 00:40:33,477 2 LOG DROP AND NORMALIZATION OF 1190 00:40:33,477 --> 00:40:33,677 ALT. 1191 00:40:33,677 --> 00:40:35,446 AS YOU CAN SEE THIS DATA WOULD 1192 00:40:35,446 --> 00:40:37,648 SUGGEST THAT MOST OF THESE 1193 00:40:37,648 --> 00:40:41,819 PEOPLE HAVE ACHIEVED -- A LARGE 1194 00:40:41,819 --> 00:40:43,320 NUMBER OF PATIENTS HAVE 2 LOG 1195 00:40:43,320 --> 00:40:45,189 DROP EVEN IN REAL LIFE SCENARIO. 1196 00:40:45,189 --> 00:40:48,492 SO THAT'S BEEN WIDELY USED IN 1197 00:40:48,492 --> 00:40:54,732 EUROPEAN STUDIES AND MANY HAVE 1198 00:40:54,732 --> 00:40:57,268 STARTED -- IT CAN BE EXTENDED TO 1199 00:40:57,268 --> 00:40:58,235 96 WEEKS OF TREATMENT SO YOU'RE 1200 00:40:58,235 --> 00:41:00,104 TALKING ABOUT TWO YEARS OF 1201 00:41:00,104 --> 00:41:00,871 TREATMENT COMBINED WITH IT. 1202 00:41:00,871 --> 00:41:02,840 MANY OF THESE PEOPLE WILL HAVE 1203 00:41:02,840 --> 00:41:04,375 REBOUND EFFECTS WHEN YOU STOP 1204 00:41:04,375 --> 00:41:05,476 TREATMENT, BUT WHILE YOU'RE ON 1205 00:41:05,476 --> 00:41:06,877 TREATMENT, YOU CAN ACTUALLY HAVE 1206 00:41:06,877 --> 00:41:09,413 DECLINE IN VIRAL LOAD AS LESS 1207 00:41:09,413 --> 00:41:10,848 DECLINE IN NORMALIZATION OF ALT 1208 00:41:10,848 --> 00:41:14,218 SO YOU CAN HAVE NO PROGRESSION 1209 00:41:14,218 --> 00:41:16,787 OF FIBROSIS. 1210 00:41:16,787 --> 00:41:23,961 THE SECOND THERAPEUTIC -- ANDREW 1211 00:41:23,961 --> 00:41:25,396 WHO DISCOVERED THIS COMPOUND 1212 00:41:25,396 --> 00:41:26,163 COMPLAINS ABOUT THIS. 1213 00:41:26,163 --> 00:41:29,366 THIS IS A MOLECULE FOR A COMPANY 1214 00:41:29,366 --> 00:41:31,669 FROM CANADA WHO HAS THIS DRUG 1215 00:41:31,669 --> 00:41:34,038 DEVELOPED FOR MANY YEARS, FOR 20 1216 00:41:34,038 --> 00:41:37,908 YEARS AGO FOR HEPATITIS B. 1217 00:41:37,908 --> 00:41:39,243 -- EXACT MECHANISM IS NOT CLEAR 1218 00:41:39,243 --> 00:41:40,444 BUT NOW THERE IS MORE EVIDENCE 1219 00:41:40,444 --> 00:41:44,815 TO SUGGEST IT'S ACTUALLY 1220 00:41:44,815 --> 00:41:46,350 ASSEMBLED AND PACKAGED -- THESE 1221 00:41:46,350 --> 00:41:48,219 WERE THE MECHANISM OF ACTION, SO 1222 00:41:48,219 --> 00:41:49,620 AGAIN REDUCE THE VIRAL LOAD 1223 00:41:49,620 --> 00:41:50,221 GIVEN FOR THAT. 1224 00:41:50,221 --> 00:41:53,057 THE STUDIES WAS DONE IN 1225 00:41:53,057 --> 00:41:56,460 BANGLADESH AND MOLDOVA, B 1226 00:41:56,460 --> 00:41:57,995 SURFACE ANTIGEN AND 1227 00:41:57,995 --> 00:41:58,863 NORMALIZATION IN PATIENTS 1228 00:41:58,863 --> 00:42:01,599 TREATED EVEN SOME PEOPLE WITH 1229 00:42:01,599 --> 00:42:02,132 SEROCONVERSION. 1230 00:42:02,132 --> 00:42:03,234 THE PARTICULAR STUDY WENT BACK 1231 00:42:03,234 --> 00:42:04,902 AND LOOKED AT PEOPLE WHO HAVE 1232 00:42:04,902 --> 00:42:08,105 HEPATITIS D DELTA COINFECTION. 1233 00:42:08,105 --> 00:42:09,506 THESE ARE PATIENTS WHO ALSO HAD 1234 00:42:09,506 --> 00:42:09,840 DELTA. 1235 00:42:09,840 --> 00:42:11,809 YOU CAN SEE THE DELTA VIRAL LOAD 1236 00:42:11,809 --> 00:42:15,546 IS GOING DOWN ON ALMOST ALL OF 1237 00:42:15,546 --> 00:42:16,313 THOSE PATIENTS. 1238 00:42:16,313 --> 00:42:19,383 THEY IT NOT FOLLOW THE IMIEPED 1239 00:42:19,383 --> 00:42:21,919 RESPONSE BUT IT DOES HAVE 1240 00:42:21,919 --> 00:42:23,120 ACTIVITY AGAINST HEPATITIS DELTA 1241 00:42:23,120 --> 00:42:25,723 AS WELL. 1242 00:42:25,723 --> 00:42:27,591 THE THIRD ONE IS PROBABLY THE 1243 00:42:27,591 --> 00:42:30,461 MOST INTERESTING 1244 00:42:30,461 --> 00:42:31,328 MECHANISTICALLY. 1245 00:42:31,328 --> 00:42:35,266 THIS BLOCKS THE -- IT IS SAID 1246 00:42:35,266 --> 00:42:38,002 THE SMALL ANTIGEN BECOMES THE 1247 00:42:38,002 --> 00:42:40,204 LARGE ANTIGEN, AND THE 1248 00:42:40,204 --> 00:42:41,839 MODIFICATION IS PREVENTED. 1249 00:42:41,839 --> 00:42:42,940 THAT IS IMPORTANT BECAUSE A 1250 00:42:42,940 --> 00:42:45,142 LARGE MOLECULE, IT'S REQUIRED 1251 00:42:45,142 --> 00:42:47,678 FOR THE ASSEMBLY OF THE 1252 00:42:47,678 --> 00:42:49,647 HEPATITIS D DELTA, SO BLOCKING 1253 00:42:49,647 --> 00:42:53,350 THIS HAD GREAT FUNCTION. 1254 00:42:53,350 --> 00:42:56,887 MOST OF YOU KNOW HE'S APPROVED 1255 00:42:56,887 --> 00:42:59,490 ALREADY FOR PROGERIA. 1256 00:42:59,490 --> 00:43:02,459 THE MAIN CULPRIT OF AXILLARY 1257 00:43:02,459 --> 00:43:08,599 AGING UNDERGOES -- AND WILL LEAD 1258 00:43:08,599 --> 00:43:10,334 TO WORSENING OF CARDIOVASCULAR 1259 00:43:10,334 --> 00:43:11,235 MORTALITY SO IT'S ALREADY 1260 00:43:11,235 --> 00:43:14,838 APPROVED FOR THAT PARTICULAR 1261 00:43:14,838 --> 00:43:17,775 THING. 1262 00:43:17,775 --> 00:43:18,909 THIS IS A CROWDED SLIDE, THIS IS 1263 00:43:18,909 --> 00:43:23,013 A STUDY THAT LED TO MULTIPLE 1264 00:43:23,013 --> 00:43:24,581 DIFFERENT THINGS, MULTIPLE 1265 00:43:24,581 --> 00:43:27,017 DIFFERENT DOSES WERE TESTED, 1266 00:43:27,017 --> 00:43:31,522 MULTIPLE DURATIONED WERE TESTED. 1267 00:43:31,522 --> 00:43:33,390 IN THE STUDY OF RESULTS, IF YOU 1268 00:43:33,390 --> 00:43:40,164 LOOK AT 25 MG AND 50 MG DOSING 1269 00:43:40,164 --> 00:43:44,768 DOSING -- IT HAS POOR -- 1270 00:43:44,768 --> 00:43:47,304 COMBINED WITH -- SO IT CAN 1271 00:43:47,304 --> 00:43:51,442 PROLONG THE CONCENTRATION OF 1272 00:43:51,442 --> 00:43:57,381 LOLONAFARNIB, SIMILAR TO YOU THT 1273 00:43:57,381 --> 00:43:59,683 HAVE TAKEN PAXLOVID FOR COVID. 1274 00:43:59,683 --> 00:44:01,218 YOU TAKE THIS, DO YOU THAT, THE 1275 00:44:01,218 --> 00:44:02,686 HIGHER DOSE DEFINITELY HAVE A 1276 00:44:02,686 --> 00:44:05,022 TWO LOG DECLINE AT THE END OF 24 1277 00:44:05,022 --> 00:44:06,390 WEEKS. 1278 00:44:06,390 --> 00:44:07,658 IF UP USE INTERFERON IN ADDITION 1279 00:44:07,658 --> 00:44:09,893 TO THAT, THEN YOU'RE ACTUALLY 1280 00:44:09,893 --> 00:44:15,065 HAVING ALMOST A 2.67 LOG DROP OF 1281 00:44:15,065 --> 00:44:15,933 ANTIVIRAL ACTIVITIES. 1282 00:44:15,933 --> 00:44:19,236 HIGHER DOSING, 50 MG DOSE, 1283 00:44:19,236 --> 00:44:21,305 YOU'RE GETTING CLOSE TO FOUR LOG 1284 00:44:21,305 --> 00:44:22,639 DROP IN 24 WEEKS. 1285 00:44:22,639 --> 00:44:26,143 IT IS A GOOD ANTIVIRAL AGENT 1286 00:44:26,143 --> 00:44:28,245 THAT HAS COMBINATIONS FOR THAT. 1287 00:44:28,245 --> 00:44:30,114 THE CONCERN IS THAT YOU HAVE TO 1288 00:44:30,114 --> 00:44:39,089 COMBINE WITH R -- DEFINITELY ISN 1289 00:44:39,089 --> 00:44:40,991 ORAL AGENT, IT HAS AN ADVANTAGE. 1290 00:44:40,991 --> 00:44:42,993 TO COMBINATIONS OF THAT, JUST TO 1291 00:44:42,993 --> 00:44:44,194 COMPARE THESE AGENTS WITH THE 1292 00:44:44,194 --> 00:44:49,566 THERAPEUTICS WE HAVE, LONAFARNIB 1293 00:44:49,566 --> 00:44:54,972 IS POTENTIALLY SHORT -- ALLOW 1294 00:44:54,972 --> 00:44:57,041 DAILY DOSING. 1295 00:44:57,041 --> 00:45:01,278 BUT DRUG AND DRUG INTERACTIONS 1296 00:45:01,278 --> 00:45:02,546 WITH -- IS A HUGE NIGHTMARE. 1297 00:45:02,546 --> 00:45:05,082 YOU CANNOT COMBINE THEM WITH 1298 00:45:05,082 --> 00:45:07,785 MANY OTHER MEDICATIONS AND FOR A 1299 00:45:07,785 --> 00:45:09,119 LONG PERIOD OF TIME FOR 24 WEEKS 1300 00:45:09,119 --> 00:45:10,020 IS DEFINITELY CONCERNING. 1301 00:45:10,020 --> 00:45:11,555 BUT IT ALSO -- MOST OF THESE 1302 00:45:11,555 --> 00:45:14,191 DRUGS HAVE NOT BEEN USED WITH -- 1303 00:45:14,191 --> 00:45:16,393 PATIENTS SO YOU CANNOT REALLY 1304 00:45:16,393 --> 00:45:18,028 HAVE SAFETY DAY IT ON THAT, 1305 00:45:18,028 --> 00:45:20,330 CAN'T USE MEDICATION ON THAT. 1306 00:45:20,330 --> 00:45:21,765 SIDE EFFECTS ARE DEFINITELY 1307 00:45:21,765 --> 00:45:22,032 IMPORTANT. 1308 00:45:22,032 --> 00:45:23,333 GENERAL CONSIDERATIONS YOU CAN 1309 00:45:23,333 --> 00:45:24,535 USE -- STILL NEED TO DEFINE HOW 1310 00:45:24,535 --> 00:45:26,403 LONG YOU NEED TO TREAT TO CURE 1311 00:45:26,403 --> 00:45:30,174 HEPATITIS DELTA. 1312 00:45:30,174 --> 00:45:32,776 LONG TERM DATA IS NOT THERE. 1313 00:45:32,776 --> 00:45:34,078 INJECTABLE, SUBCUTANEOUS 1314 00:45:34,078 --> 00:45:36,180 INJECTABLE DAILY INJECTION, AND 1315 00:45:36,180 --> 00:45:37,314 THAT HAS GOOD TOLERABILITY IN 1316 00:45:37,314 --> 00:45:38,682 THE STUDIES BUT STILL AN 1317 00:45:38,682 --> 00:45:39,483 INJECTION. 1318 00:45:39,483 --> 00:45:40,250 TAKING PEOPLE WHO HAVE NO 1319 00:45:40,250 --> 00:45:41,718 SYMPTOMS AND GIVING THEM 1320 00:45:41,718 --> 00:45:42,886 INJECTION FOR A YEAR OR TWO 1321 00:45:42,886 --> 00:45:44,955 YEARS IS NOT GOING TO BE EASY TO 1322 00:45:44,955 --> 00:45:45,355 DO. 1323 00:45:45,355 --> 00:45:48,959 IT ALSO HAS NO SAFETY DATA ON 1324 00:45:48,959 --> 00:45:51,395 CIRRHOSIS PATIENTS AND TREATMENT 1325 00:45:51,395 --> 00:45:52,529 DURATIONS, WE DON'T REALLY HAVE 1326 00:45:52,529 --> 00:45:53,564 GOOD DAY IT ON WHAT HAPPENS 1327 00:45:53,564 --> 00:45:58,035 AFTER STOPPING TREATMENT FOR 1328 00:45:58,035 --> 00:46:02,539 SUSTAINED RESPONSE. 1329 00:46:02,539 --> 00:46:08,145 PEG INTERFERON ALPHA IS THE MOST 1330 00:46:08,145 --> 00:46:09,646 LONG TERM SPEENS, WE ALSO HAVE 1331 00:46:09,646 --> 00:46:12,282 GOOD DATA ON LONG TERM OUTCOMES 1332 00:46:12,282 --> 00:46:13,517 IMPROVEMENT WITH THE HEPATITIS 1333 00:46:13,517 --> 00:46:13,750 DELTA. 1334 00:46:13,750 --> 00:46:16,253 THE CONCERN WITH INTERFERON 1335 00:46:16,253 --> 00:46:17,454 ALPHA IS ALWAYS THE SIDE EFFECT 1336 00:46:17,454 --> 00:46:17,888 PROFILE. 1337 00:46:17,888 --> 00:46:19,456 IT HAS SIDE EFFECTS WHEN YOU 1338 00:46:19,456 --> 00:46:20,357 TAKE IT FOR A LONG PERIOD OF 1339 00:46:20,357 --> 00:46:21,658 TIME, IT BECOMES INTOLERABLE 1340 00:46:21,658 --> 00:46:23,961 MOST OF THE TIME. 1341 00:46:23,961 --> 00:46:25,562 PEG INTERFERON LAMBDA IS AN 1342 00:46:25,562 --> 00:46:27,598 OPTION, IT MAY HAVE SLIDELY 1343 00:46:27,598 --> 00:46:29,133 DIFFERENT SIDE EFFECTS BUT IT'S 1344 00:46:29,133 --> 00:46:33,003 ALSO NOT APPROVED FOFER FOR HEPS 1345 00:46:33,003 --> 00:46:33,537 DELTA. 1346 00:46:33,537 --> 00:46:34,638 TO SUMMARIZE, THERE ARE MULTIPLE 1347 00:46:34,638 --> 00:46:35,939 DIFFERENT STRATEGIES AVAILABLE. 1348 00:46:35,939 --> 00:46:37,307 THESE STRATEGIES LEAD TO 1349 00:46:37,307 --> 00:46:39,476 SIGNIFICANT DECLINE IN HDV. 1350 00:46:39,476 --> 00:46:40,911 IT IS NOT CLEAR WHETHER THIS 1351 00:46:40,911 --> 00:46:42,212 WILL LEAD TO FUNCTIONAL CURE. 1352 00:46:42,212 --> 00:46:44,014 PATIENTS HAVE TO GO OFF 1353 00:46:44,014 --> 00:46:45,649 TREATMENT AND THEN ONLY WE WILL 1354 00:46:45,649 --> 00:46:46,416 KNOW THAT THEY HAVE. 1355 00:46:46,416 --> 00:46:48,118 BUT THERE IS STILL AN ADVANTAGE 1356 00:46:48,118 --> 00:46:52,923 OF TREATING PATIENTS OF SUCH AN 1357 00:46:52,923 --> 00:46:55,025 AGGRESSIVE DISEASE AND ARRESTING 1358 00:46:55,025 --> 00:46:56,727 THE DISEASE WILL BE USEFUL FOR 1359 00:46:56,727 --> 00:46:58,862 MOST OF THESE PATIENTS. 1360 00:46:58,862 --> 00:47:02,466 MANY OF THESE STRATEGIES REQUIRE 1361 00:47:02,466 --> 00:47:05,836 ADDITIONAL ADDING PEG INTERFERON 1362 00:47:05,836 --> 00:47:09,006 WHICH -- LACK OF -- FOR 1363 00:47:09,006 --> 00:47:09,907 HEPATITIS B SO THERE'S ALWAYS 1364 00:47:09,907 --> 00:47:11,341 THIS THING IF YOU CAN CURE 1365 00:47:11,341 --> 00:47:12,442 HEPATITIS B YOU WON'T HAVE 1366 00:47:12,442 --> 00:47:13,777 HEPATITIS DELTA. 1367 00:47:13,777 --> 00:47:14,978 WE HAVE NOT MADE SUCCESS THERE 1368 00:47:14,978 --> 00:47:16,079 SO THAT'S REALLY NOT AN OPTION 1369 00:47:16,079 --> 00:47:17,347 BUT THAT IS DEFINITELY ONE OF 1370 00:47:17,347 --> 00:47:19,783 THE OPTIONS IF YOU HAVE A 1371 00:47:19,783 --> 00:47:21,919 METHODOLOGY TO -- OR A TREATMENT 1372 00:47:21,919 --> 00:47:23,320 PARADIGM THAT WILL CLEAR YOUR 1373 00:47:23,320 --> 00:47:26,056 HEPATITIS B. 1374 00:47:26,056 --> 00:47:27,391 CORRELATES OF CLEARANCE OF DELTA 1375 00:47:27,391 --> 00:47:29,493 ARE NOT CLEAR SO THAT'S ALSO 1376 00:47:29,493 --> 00:47:31,361 COMPLICATED, THAT HOW REALLY TO 1377 00:47:31,361 --> 00:47:33,197 DEFINE WHEN TO STOP TREATMENT 1378 00:47:33,197 --> 00:47:34,565 FOR THESE PATIENTS, IT'S NOT 1379 00:47:34,565 --> 00:47:35,766 VERY CLEARLY UNDERSTOOD, AND 1380 00:47:35,766 --> 00:47:40,137 THAT BECOME AS HUGE CHALLENGE IN 1381 00:47:40,137 --> 00:47:40,804 DECIDING CLINICAL TRIALS FOR 1382 00:47:40,804 --> 00:47:42,239 FUNCTIONAL CURE. 1383 00:47:42,239 --> 00:47:43,340 SO LOOKING AT THIS PARTICULAR 1384 00:47:43,340 --> 00:47:44,942 ASPECT OF IT, HOW WE UNDERSTAND 1385 00:47:44,942 --> 00:47:46,476 THE CORRELATES OF CURE FOR 1386 00:47:46,476 --> 00:47:48,278 HEPATITIS C ONE WAY WE TRY TO 1387 00:47:48,278 --> 00:47:50,480 UNDERSTAND IS TO DEVELOP 1388 00:47:50,480 --> 00:47:53,183 HUMANIZED MOUSE MODEL, SO 1389 00:47:53,183 --> 00:47:56,620 ACTUALLY HAVE -- IN 1390 00:47:56,620 --> 00:47:58,288 COLLABORATION, WE HAVE SEVERAL 1391 00:47:58,288 --> 00:48:02,192 OF THE YO HUMANIZED MOUSE MODELO 1392 00:48:02,192 --> 00:48:06,196 TAKE A MOUSE WITH LESS IMMUNITY 1393 00:48:06,196 --> 00:48:08,865 AND WE CONSIDER THE MOUSE WITH 1394 00:48:08,865 --> 00:48:11,401 HUMAN IMMUNE SYSTEM -- STEM 1395 00:48:11,401 --> 00:48:11,902 CELLS. 1396 00:48:11,902 --> 00:48:14,438 SO THAT REALLY COSTS THE IMMUNE 1397 00:48:14,438 --> 00:48:22,679 SYSTEM TO SOME EXTENT, AND -- SO 1398 00:48:22,679 --> 00:48:25,682 SLOWLY YOU CAN REPLACE THE MOUSE 1399 00:48:25,682 --> 00:48:27,918 LIVER WITH FETAL HUMAN LIVER. 1400 00:48:27,918 --> 00:48:29,286 WITH THIS, IT'S TRICKY, MOST 1401 00:48:29,286 --> 00:48:30,821 PEOPLE CANNOT DO, ONCE YOU HAVE 1402 00:48:30,821 --> 00:48:33,156 A HUMAN LIVER, YOU CAN INFECT 1403 00:48:33,156 --> 00:48:34,024 THEM WITH HEPATITIS B OR INFECT 1404 00:48:34,024 --> 00:48:35,659 THEM WITH HEPATITIS DELTA AND 1405 00:48:35,659 --> 00:48:36,760 DEVELOP CHRONIC DISEASE. 1406 00:48:36,760 --> 00:48:38,228 ANIMAL MODELS AS YOU ALL KNOW 1407 00:48:38,228 --> 00:48:39,196 HAS ISSUES WITH THAT. 1408 00:48:39,196 --> 00:48:42,065 SOME OF THE ADVANTAGES -- 1409 00:48:42,065 --> 00:48:45,435 EASILY, QUICKLY, QUICKLY STUDY 1410 00:48:45,435 --> 00:48:47,037 THE EFFICACY OF VIRAL AGENTS BUT 1411 00:48:47,037 --> 00:48:49,606 IT DOESN'T REALLY TRANSLATE INTO 1412 00:48:49,606 --> 00:48:51,508 LONG TERM HUMAN MODEL, NOT 1413 00:48:51,508 --> 00:48:53,210 SIMILAR TO HUMAN WITH HEPATITIS 1414 00:48:53,210 --> 00:48:55,145 DELTA. 1415 00:48:55,145 --> 00:48:58,782 SO WE HAVE TO USE -- 1416 00:48:58,782 --> 00:48:59,783 METHODOLOGIES TO MAKE THEM 1417 00:48:59,783 --> 00:49:00,984 DEVELOP CANCER AND THAT'S REALLY 1418 00:49:00,984 --> 00:49:02,653 NOT IDEAL. 1419 00:49:02,653 --> 00:49:04,688 SO LET'S GO AND FIND PEOPLE WHO 1420 00:49:04,688 --> 00:49:06,056 HAVE CLEAR HEPATITIS DELTA AND 1421 00:49:06,056 --> 00:49:08,125 FIND WHAT'S GOING ON IN THEM 1422 00:49:08,125 --> 00:49:10,093 IMMUNOLOGICALLY AND THEN WE'LL 1423 00:49:10,093 --> 00:49:10,861 UNDERSTAND -- INFORM OUR 1424 00:49:10,861 --> 00:49:11,695 UNDERSTANDING ABOUT WHAT 1425 00:49:11,695 --> 00:49:12,763 CORRELATES OF PROTECTIONS ARE 1426 00:49:12,763 --> 00:49:13,330 THERE. 1427 00:49:13,330 --> 00:49:17,134 SO WE WENT BACK TO MONGOLIA AND 1428 00:49:17,134 --> 00:49:20,137 FROM ANOTHER -- ONE OF MY 1429 00:49:20,137 --> 00:49:22,806 FELLOWS ACTUALLY WENT TO 1430 00:49:22,806 --> 00:49:24,975 MONGOLIA TO ESTABLISH A COHORT 1431 00:49:24,975 --> 00:49:27,144 THERE, ISTANBUL AND ALSO 1432 00:49:27,144 --> 00:49:28,912 PAKISTAN, AND WE GOT SAMPLES. 1433 00:49:28,912 --> 00:49:31,782 THIS IS PRIMARILY -- WE LOOKED 1434 00:49:31,782 --> 00:49:33,750 AT THREE GROUPS OF PEOPLE, THE 1435 00:49:33,750 --> 00:49:35,285 PEOPLE WHO HAVE BOTH CHRONIC 1436 00:49:35,285 --> 00:49:37,587 HEPATITIS B AND DELTA, CLEAR 1437 00:49:37,587 --> 00:49:40,190 DELTA ALONE BUT THEY HAVE 1438 00:49:40,190 --> 00:49:41,658 CHRONIC HEPATITIS B AND -- AND 1439 00:49:41,658 --> 00:49:46,263 THEY LOOK AT PHENOTYPING WHAT'S 1440 00:49:46,263 --> 00:49:50,033 DIFFERENT IN THE PHENOTYPING, 1441 00:49:50,033 --> 00:49:55,172 HEPATITIS B, HEPATITIS DELTA, 1442 00:49:55,172 --> 00:49:59,142 RNA, BULK RNA SEQ -- AS YOU KNOW 1443 00:49:59,142 --> 00:50:00,143 THE DIFFERENCE HERE IS MAINLY 1444 00:50:00,143 --> 00:50:02,979 THE ALT LEVELS, OTHERWISE THEY 1445 00:50:02,979 --> 00:50:04,214 ARE USUALLY MATCHED AND THEY'RE 1446 00:50:04,214 --> 00:50:05,349 NOT REALLY SIGNIFICANTLY 1447 00:50:05,349 --> 00:50:06,316 DIFFERENT FROM OTHER ASPECTS OF 1448 00:50:06,316 --> 00:50:07,417 IT. 1449 00:50:07,417 --> 00:50:09,586 SO JUST TO GIVE A BRIEF 1450 00:50:09,586 --> 00:50:10,954 HIGHLIGHT IS THAT ONE THING WE 1451 00:50:10,954 --> 00:50:14,458 FIND IS THAT THE CD8 CELLS 1452 00:50:14,458 --> 00:50:15,892 SUPPRESSING LOW LEVELS OF 1453 00:50:15,892 --> 00:50:20,530 INHIBITORY MOLECULES, AND 1454 00:50:20,530 --> 00:50:23,700 CTLA4 SIGNIFICANTLY REDUCED. 1455 00:50:23,700 --> 00:50:25,001 THEN PEOPLE WHO HAVE CHRONIC 1456 00:50:25,001 --> 00:50:28,872 HEPATITIS DELTA HAVE THESE 1457 00:50:28,872 --> 00:50:30,974 CD8 CELLS EXPRESSING THESE 1458 00:50:30,974 --> 00:50:32,743 INHIBITORY MOLECULES, PREVENTING 1459 00:50:32,743 --> 00:50:33,777 THEM FROM FUNCTIONING WHAT 1460 00:50:33,777 --> 00:50:35,812 THEY'RE SUPPOSED TO DO. 1461 00:50:35,812 --> 00:50:38,882 WHEN WE LOOK AT REPEAT 1462 00:50:38,882 --> 00:50:40,183 RESTIMULATION, WE TAKE BOTH 1463 00:50:40,183 --> 00:50:41,518 HEPATITIS B SPECIFIC AND D 1464 00:50:41,518 --> 00:50:46,923 SPECIFIC STIMULATION, THEN -- 1465 00:50:46,923 --> 00:50:49,226 WITH HIV SPECIFIC PEPTIDES FOR 1466 00:50:49,226 --> 00:50:59,736 NINE DAYS, LOOK FOR ANTIVIRAL 1467 00:51:01,071 --> 00:51:01,271 CYTOKINES. 1468 00:51:01,271 --> 00:51:01,805 YOU SEE PEOPLE WHO CREATE 1469 00:51:01,805 --> 00:51:02,339 HEPATITIS DELTA MAKE MORE 1470 00:51:02,339 --> 00:51:02,839 CYTOKINES IN RESPONSE TO 1471 00:51:02,839 --> 00:51:03,440 STIMULATION WITH -- SPECIFIC 1472 00:51:03,440 --> 00:51:03,974 RESPONSE IS ACCELERATED. 1473 00:51:03,974 --> 00:51:05,442 THIS HAS BEEN SHOWN BY -- FOR 1474 00:51:05,442 --> 00:51:08,111 HEPATITIS B AND MANY OTHER DIES 1475 00:51:08,111 --> 00:51:09,379 DISEASE, HEPATITIS C, AS WELL AS 1476 00:51:09,379 --> 00:51:13,150 DEMONSTRATED MANY OTHER -- WHEN 1477 00:51:13,150 --> 00:51:15,185 YOU CLEAR YOU ALSO DEVELOP 1478 00:51:15,185 --> 00:51:16,086 IMMUNE RESPONSE AGAINST THAT 1479 00:51:16,086 --> 00:51:17,954 PARTICULAR VIRUS. 1480 00:51:17,954 --> 00:51:20,524 IT'S A CAUSE AND EFFECT, 1481 00:51:20,524 --> 00:51:24,561 SOMETHING DIFFICULT TO -- TNF 1482 00:51:24,561 --> 00:51:26,596 ALPHA PRODUCTION, 1483 00:51:26,596 --> 00:51:26,963 IL21 PRODUCTION. 1484 00:51:26,963 --> 00:51:28,198 WHEN WE LOOK AT WHETHER THEY 1485 00:51:28,198 --> 00:51:30,834 MAKE MULTIPLE CYTOKINES, THEY DO 1486 00:51:30,834 --> 00:51:34,137 ACTUALLY MAKE -- THEY MAKE 1487 00:51:34,137 --> 00:51:37,107 IL2 AND TNF, AND INTERFERON 1488 00:51:37,107 --> 00:51:38,642 GAMMA, THEY MAKE MULTIPLE 1489 00:51:38,642 --> 00:51:42,612 DIFFERENT CYTOKINES BUT -- 1490 00:51:42,612 --> 00:51:44,147 GENERALLY WE BELIEVE THAT THE 1491 00:51:44,147 --> 00:51:46,116 CELLS MAKE MULTIPLE DIFFERENT 1492 00:51:46,116 --> 00:51:47,017 CYTOKINES BETTER EVEN THOUGH 1493 00:51:47,017 --> 00:51:48,285 THERE IS NO CLINICAL CORRELATION 1494 00:51:48,285 --> 00:51:50,420 THAT THIS ACTUALLY -- INTO ANY 1495 00:51:50,420 --> 00:51:52,055 KIND OF CLINICAL PARADIGM. 1496 00:51:52,055 --> 00:51:53,824 BULK RNA SEQ ALSO CLEARLY 1497 00:51:53,824 --> 00:51:55,292 DEMONSTRATED PATHWAYS THAT 1498 00:51:55,292 --> 00:51:56,593 IMPROVED T-CELL FUNCTION. 1499 00:51:56,593 --> 00:51:59,262 THOSE ARE THE PRIMARY PATHWAYS 1500 00:51:59,262 --> 00:52:07,304 IN THE PEOPLE WHO CLEAR DELTA -- 1501 00:52:07,304 --> 00:52:07,904 OR THE TCR SIGNALING FUNCTION 1502 00:52:07,904 --> 00:52:09,339 AND HAS DECEL FUNCTION WAS THE 1503 00:52:09,339 --> 00:52:09,673 KEY SIGNATURE. 1504 00:52:09,673 --> 00:52:11,575 THAT LED US TO GO BACK AND LOOK 1505 00:52:11,575 --> 00:52:15,078 AT SINGLE CELL RNA -- WITH 1506 00:52:15,078 --> 00:52:16,613 DELTA, SPECIFICALLY CD8 CELLS, 1507 00:52:16,613 --> 00:52:19,916 THEN LOOK AT SOME -- I THINK 1508 00:52:19,916 --> 00:52:22,986 HERE -- THE PATHWAYS INCREASED 1509 00:52:22,986 --> 00:52:24,654 ANTIVIRAL GENES INCREASED T-CELL 1510 00:52:24,654 --> 00:52:29,626 RECEPTOR FUNCTION, AND REDUCTION 1511 00:52:29,626 --> 00:52:31,127 IN IMMUNOSUPPRESSIVE AND -- 1512 00:52:31,127 --> 00:52:31,561 GENES. 1513 00:52:31,561 --> 00:52:33,864 SO THOSE OF MEES FUNCTIONS 1514 00:52:33,864 --> 00:52:36,633 CORRELATED WITH IMPROVED DELTA 1515 00:52:36,633 --> 00:52:37,834 SPECIFIC IMMUNOLOGICAL FUNCTION 1516 00:52:37,834 --> 00:52:40,470 AND RECOVERY FROM THE EFFECT OF 1517 00:52:40,470 --> 00:52:44,774 CHRONIC VIRAL EXHAUSTION AT D 1518 00:52:44,774 --> 00:52:45,642 CELL PHENOTYPE. 1519 00:52:45,642 --> 00:52:49,613 TO SUMMARIZE, RECUSED 1520 00:52:49,613 --> 00:52:52,382 EXHAUSTION, POLYFUNCTIONALITY, 1521 00:52:52,382 --> 00:52:53,650 PROLIFERATION, PRODUCTION OF 1522 00:52:53,650 --> 00:52:54,484 DIFFERENT CYTOKINES. 1523 00:52:54,484 --> 00:52:58,855 SO IN SUMMARY, GENE 1524 00:52:58,855 --> 00:53:00,257 SIGNATURES -- ENHANCE DE FACTO 1525 00:53:00,257 --> 00:53:07,564 MEMORY NEEN T PHENOTYPE -- IMPR- 1526 00:53:07,564 --> 00:53:08,231 CD4CD8 FUNCTION. 1527 00:53:08,231 --> 00:53:09,866 THE CHALLENGE IS THAT YES, THIS 1528 00:53:09,866 --> 00:53:11,434 IS A CROSS-SECTIONAL STUDY BUT 1529 00:53:11,434 --> 00:53:13,436 HOW DO YOU REALLY RELATE TO 1530 00:53:13,436 --> 00:53:14,304 IMMUNOLOGICAL END POINT TO GUIDE 1531 00:53:14,304 --> 00:53:14,771 TREATMENT? 1532 00:53:14,771 --> 00:53:15,739 IT'S VERY DIFFICULT TO DO. 1533 00:53:15,739 --> 00:53:17,173 BECAUSE THERE IS NO CUT POINT 1534 00:53:17,173 --> 00:53:18,475 LIKE A VIRAL LOAD, YOU CAN 1535 00:53:18,475 --> 00:53:19,976 ACTUALLY HAVE A DETECTABLE -- 1536 00:53:19,976 --> 00:53:21,011 MUCH MORE DIFFICULT TO DO. 1537 00:53:21,011 --> 00:53:22,679 OUR NEXT STEP WOULD BE TO STUDY 1538 00:53:22,679 --> 00:53:24,147 IN THE CONTEXT OF TREATMENT OF 1539 00:53:24,147 --> 00:53:26,483 PATIENTS AND TRY TO VALIDATE 1540 00:53:26,483 --> 00:53:28,318 THAT WITH THE RESPONSE TO 1541 00:53:28,318 --> 00:53:30,387 CLINICAL OUT COME IN A 1542 00:53:30,387 --> 00:53:31,154 RESPECTIVE MANNER. 1543 00:53:31,154 --> 00:53:33,723 ONCE WE DO THAT WE CAN 1544 00:53:33,723 --> 00:53:35,825 DEVELOP -- THAT WILL HELP US TO 1545 00:53:35,825 --> 00:53:37,460 SAY -- AND YOU CAN ACTUALLY STOP 1546 00:53:37,460 --> 00:53:38,695 THE TREATMENT AND THEY WOULD BE 1547 00:53:38,695 --> 00:53:40,997 ABLE TO GET BETTER. 1548 00:53:40,997 --> 00:53:42,666 SO TO CONCLUDE THE SCREENING FOR 1549 00:53:42,666 --> 00:53:44,668 HEPATITIS DELTA IS NOT ROUTINELY 1550 00:53:44,668 --> 00:53:48,171 FOREMANNEDPERFORMED AND COULD PA 1551 00:53:48,171 --> 00:53:49,673 CHALLENGE WITH NEW PATIENTS. 1552 00:53:49,673 --> 00:53:50,907 THIS IS ONE OF THE REASONS WHY 1553 00:53:50,907 --> 00:53:52,809 THIS IS NOT APPROVED BY THE U.S. 1554 00:53:52,809 --> 00:53:54,744 FDA BECAUSE WE HAVE SO MANY 1555 00:53:54,744 --> 00:53:55,946 UNKNOWNS ABOUT DELTA PATIENTS IN 1556 00:53:55,946 --> 00:53:56,479 THE UNITED STATES. 1557 00:53:56,479 --> 00:54:00,116 WE DON'T REALLY HAVE A -- PCR 1558 00:54:00,116 --> 00:54:02,018 TESTING, WE DON'T KNOW THE 1559 00:54:02,018 --> 00:54:02,752 GENOTYPE DISTRIBUTION VERY WELL. 1560 00:54:02,752 --> 00:54:04,187 THERE'S SO MANY UNKNOWNS ABOUT 1561 00:54:04,187 --> 00:54:04,621 THIS. 1562 00:54:04,621 --> 00:54:06,222 SO WHO ARE THE PEOPLE HA ARE 1563 00:54:06,222 --> 00:54:09,593 GOING TO BENEFIT IS NOT KNOWN. 1564 00:54:09,593 --> 00:54:13,263 THIS DRUG WAS APPROVED IN THE 1565 00:54:13,263 --> 00:54:15,665 EUROPEAN UNION YEARS AGO. 1566 00:54:15,665 --> 00:54:17,434 THERE ARE SEVERAL THERAPEUTICS 1567 00:54:17,434 --> 00:54:21,571 COMING IN THAT WILL BLOCK HDV 1568 00:54:21,571 --> 00:54:22,472 REPLICATION AND HOPEFULLY THAT 1569 00:54:22,472 --> 00:54:24,441 WILL RELATE TO REDUCED DISEASE 1570 00:54:24,441 --> 00:54:25,976 PROGRESSION AND CARCINOGENESIS. 1571 00:54:25,976 --> 00:54:28,378 AND WE REALLY NEED A PREDICTIVE 1572 00:54:28,378 --> 00:54:29,546 ALGORITHM SO EFFICIENTLY WE CAN 1573 00:54:29,546 --> 00:54:31,514 BE LIKE HEPATITIS C, WHERE WE 1574 00:54:31,514 --> 00:54:33,583 HAVE A FUNCTIONAL KEURL PARADIGM 1575 00:54:33,583 --> 00:54:35,719 THAT CAN HAPPEN WITH THE 1576 00:54:35,719 --> 00:54:37,787 HEPATITIS DELTA, AND IT'S 1577 00:54:37,787 --> 00:54:39,189 DIFFICULT TO ACHIEVE BECAUSE OF 1578 00:54:39,189 --> 00:54:40,957 THE WAY THAT APPLICATION IS, BUT 1579 00:54:40,957 --> 00:54:43,059 THAT IS OUR ULTIMATE GOAL AND 1580 00:54:43,059 --> 00:54:44,394 HOPEFULLY AT SOME POINT, WE WILL 1581 00:54:44,394 --> 00:54:45,595 GET THIS. 1582 00:54:45,595 --> 00:54:54,471 I WANT TO ACKNOWLEDGE THESE,MOST 1583 00:54:54,471 --> 00:54:55,605 OF THE COHORT DEVELOPMENT HERE, 1584 00:54:55,605 --> 00:54:57,440 AND THE PEOPLE FROM MONGOLIA AND 1585 00:54:57,440 --> 00:54:58,842 TURKEY WHO PARTICIPATED IN THE 1586 00:54:58,842 --> 00:54:59,509 STUDIES AND THE PATIENTS. 1587 00:54:59,509 --> 00:55:01,878 THANK YOU, AND HAPPY TO TAKE 1588 00:55:01,878 --> 00:55:02,145 QUESTIONS. 1589 00:55:02,145 --> 00:55:12,322 [APPLAUSE] 1590 00:55:13,023 --> 00:55:14,557 >> THOSE WERE BOTH EXCELLENT 1591 00:55:14,557 --> 00:55:14,758 TALKS. 1592 00:55:14,758 --> 00:55:15,325 THANK YOU. 1593 00:55:15,325 --> 00:55:18,261 MY QUESTION IS AROUND NIH'S 1594 00:55:18,261 --> 00:55:23,500 RECENT PUSH TO MAXIMIZE 1595 00:55:23,500 --> 00:55:26,069 ORGANOIDS FOR RESEARCH FOR DRUG 1596 00:55:26,069 --> 00:55:28,371 DISCOVERY AND MOVING AWAY 1597 00:55:28,371 --> 00:55:29,472 FROM -- POTENTIALLY FROM ANIMAL 1598 00:55:29,472 --> 00:55:30,640 MODELS. 1599 00:55:30,640 --> 00:55:34,210 DO YOU FORESEE WITH LIVER 1600 00:55:34,210 --> 00:55:37,947 ORGANOIDS AND ARTIFICIAL 1601 00:55:37,947 --> 00:55:39,049 INTELLIGENCE, THIS IS A -- THIS 1602 00:55:39,049 --> 00:55:40,950 MAY BE AN OPTIMAL SCENARIO IN 1603 00:55:40,950 --> 00:55:44,988 TERMS OF DRUG DISCOVERY FOR 1604 00:55:44,988 --> 00:55:48,591 HEPATITIS D GIVEN THEY COULD BE 1605 00:55:48,591 --> 00:55:51,227 ORGANOIDS THAT COULD BE 1606 00:55:51,227 --> 00:55:55,265 DEVELOPED FROM PATIENTS WHO ARE 1607 00:55:55,265 --> 00:55:58,168 INFECTED WITH HEPATITIS DELTA 1608 00:55:58,168 --> 00:56:00,336 WITH DIFFERENT GENOTYPES AND TRY 1609 00:56:00,336 --> 00:56:00,937 MULTIPLE THERAPIES AT THE SAME 1610 00:56:00,937 --> 00:56:01,137 TIME? 1611 00:56:01,137 --> 00:56:04,674 >> IT A GOOD POINT -- ORGANOIDS 1612 00:56:04,674 --> 00:56:05,975 IS NOT A NEW FIELD, THERE ARE 1613 00:56:05,975 --> 00:56:07,677 SEVERAL DOING THAT, SO IT IS 1614 00:56:07,677 --> 00:56:09,979 DEFINITELY -- I JUST WANT TO 1615 00:56:09,979 --> 00:56:11,848 CLARIFY ONE POINT, THAT IT'S 1616 00:56:11,848 --> 00:56:16,186 VERY FOCUS ON ON THIR PEW TICK 1617 00:56:16,186 --> 00:56:18,488 DEVELOPMENT USING ORGANOID 1618 00:56:18,488 --> 00:56:19,789 SCREENINGS BUT A LOT OF WHAT WE 1619 00:56:19,789 --> 00:56:23,460 DO IS UNDERSTANDING -- FOR DRUG 1620 00:56:23,460 --> 00:56:25,028 DISCOVERY, YES, BUT THERE ARE 1621 00:56:25,028 --> 00:56:28,264 SORT OF LIMITATIONS, BUT THAT'S 1622 00:56:28,264 --> 00:56:29,966 ONE OF THE KEY ELEMENTS, WE 1623 00:56:29,966 --> 00:56:31,301 REALLY WANT TO UNDERSTAND THE 1624 00:56:31,301 --> 00:56:33,269 PROCESS OF CARCINOGENESIS, MUCH 1625 00:56:33,269 --> 00:56:34,771 MORE DIFFICULT TO DO IN THAT 1626 00:56:34,771 --> 00:56:36,973 KIND OF SETTING RATHER THAN IN 1627 00:56:36,973 --> 00:56:37,707 ANIMAL MODELS. 1628 00:56:37,707 --> 00:56:39,776 BUT USING ORGANOIDS IS NOT A NEW 1629 00:56:39,776 --> 00:56:41,044 THING, IT'S BEEN AROUND, YOU 1630 00:56:41,044 --> 00:56:42,245 COULD USE SCREENING PLATFORMS 1631 00:56:42,245 --> 00:56:48,284 VERY EASILY. 1632 00:56:48,284 --> 00:56:50,553 >> IF A MOTHER TRANSMITS 1633 00:56:50,553 --> 00:56:51,888 HEPATITIS D AS WELL AS HEPATITIS 1634 00:56:51,888 --> 00:56:53,590 B TO THE FETUS, HOW DOES THAT 1635 00:56:53,590 --> 00:56:54,457 INFLUENCE -- IF THAT HAPPENS, 1636 00:56:54,457 --> 00:56:55,558 HOW DOES THAT INFLUENCE THE 1637 00:56:55,558 --> 00:56:58,128 COURSE OF HEPATITIS D? 1638 00:56:58,128 --> 00:57:00,096 IT CERTAINLY IMPROVES AS THE 1639 00:57:00,096 --> 00:57:01,965 COURSE OF HEPATITIS B BUT HOW 1640 00:57:01,965 --> 00:57:02,632 ABOUT D? 1641 00:57:02,632 --> 00:57:04,167 >> SO I CAN GUESS ON THIS ONE 1642 00:57:04,167 --> 00:57:05,435 THAT USUALLY THEY WILL GET 1643 00:57:05,435 --> 00:57:07,837 CHRONIC DISEASE, BUT IF YOU HAVE 1644 00:57:07,837 --> 00:57:08,872 CHRONIC HEPATITIS B FROM THE 1645 00:57:08,872 --> 00:57:10,273 MOTHER, THERE IS HIGH LIKELIHOOD 1646 00:57:10,273 --> 00:57:12,609 THAT THE FEE CUSS CAN GET IT AND 1647 00:57:12,609 --> 00:57:15,178 THEY DEVELOP ALMOST 95% OF THOSE 1648 00:57:15,178 --> 00:57:18,348 FETUSES WILL GO ON TO DEVELOP 1649 00:57:18,348 --> 00:57:19,315 CHRONIC HEPATITIS B. 1650 00:57:19,315 --> 00:57:22,285 SO IF YOU GET BOTH AT THE SAME 1651 00:57:22,285 --> 00:57:25,188 TIME, THAT PARTICULAR GROUP OF 1652 00:57:25,188 --> 00:57:28,024 PEOPLE HAVE IMMUNITY SO THEY 1653 00:57:28,024 --> 00:57:30,760 CLEAR IT THEMSELVES. 1654 00:57:30,760 --> 00:57:34,297 DUSH -- IN THAT PARTICULAR SCE, 1655 00:57:34,297 --> 00:57:36,599 I'M NOT AWARE OF ANY LITERATURE. 1656 00:57:36,599 --> 00:57:40,937 >> ANOTHER QUESTION IS, IF 1657 00:57:40,937 --> 00:57:42,872 YOU'RE TREATING HEPATITIS C AND 1658 00:57:42,872 --> 00:57:45,108 A PERSON IS COINFECTED WITH 1659 00:57:45,108 --> 00:57:46,576 HEPATITIS B, AS YOU CONTROL THE 1660 00:57:46,576 --> 00:57:48,011 HEPATITIS C INFECTION, SOMETIMES 1661 00:57:48,011 --> 00:57:49,312 THE HEPATITIS B WILL REACTIVATE 1662 00:57:49,312 --> 00:57:50,647 AND SOMETIMES VERY SEVERELY. 1663 00:57:50,647 --> 00:57:52,615 SO IF THE PERSON IS COINFECTED 1664 00:57:52,615 --> 00:57:55,952 WITH D, DOES IT HAVE THE SAME 1665 00:57:55,952 --> 00:57:59,956 EFFECT ON B? 1666 00:57:59,956 --> 00:58:02,292 >> DID HOOFNAGLE ALWAYS 1667 00:58:02,292 --> 00:58:03,226 COMPLAINS ABOUT THIS, HE WROTE A 1668 00:58:03,226 --> 00:58:04,761 PAPER ABOUT THIS AND IT WAS 1669 00:58:04,761 --> 00:58:05,662 REJECTED MULTIPLE TIMES TO THE 1670 00:58:05,662 --> 00:58:07,230 EXTENT THAT HE NEVER ENDED UP 1671 00:58:07,230 --> 00:58:08,364 PUBLISHING IT AND WHAT HE SHOWED 1672 00:58:08,364 --> 00:58:09,966 WAS THAT IF YOU SUPPRESSED D 1673 00:58:09,966 --> 00:58:13,369 WITH INTERFERON, B WOULD FLARE. 1674 00:58:13,369 --> 00:58:15,939 AND YOU'RE CORRECT, THAT IS -- 1675 00:58:15,939 --> 00:58:17,574 AND YOU WOULD THINK THAT 1676 00:58:17,574 --> 00:58:18,474 INTERFERON SHOULD SUPPRESS BOTH, 1677 00:58:18,474 --> 00:58:19,509 BUT HE ACTUALLY SHOWED THAT 1678 00:58:19,509 --> 00:58:22,045 THERE WAS THIS DANCE BETWEEN THE 1679 00:58:22,045 --> 00:58:22,212 TWO. 1680 00:58:22,212 --> 00:58:24,414 AND TO THE EXTENT THAT TODAY, 1681 00:58:24,414 --> 00:58:26,449 WHEN WE TREAT PATIENTS FOR 1682 00:58:26,449 --> 00:58:27,984 HEPATITIS D WITH INTERFERON, WE 1683 00:58:27,984 --> 00:58:31,621 OFTEN PUT THEM ON ORAL AGENTS TO 1684 00:58:31,621 --> 00:58:32,922 TREAT HEPATITIS B TO PREVENT 1685 00:58:32,922 --> 00:58:34,290 THOSE FLARES. 1686 00:58:34,290 --> 00:58:35,592 IT'S NOT THAT THEY DO BETTER. 1687 00:58:35,592 --> 00:58:37,026 I ACTUALLY THINK THEY MAY EVEN 1688 00:58:37,026 --> 00:58:39,295 DO A LITTLE BIT WORSE. 1689 00:58:39,295 --> 00:58:40,463 WE HAVE SOME EARLY EVIDENCE FOR 1690 00:58:40,463 --> 00:58:43,533 THAT, THAT IF YOU USE TENOFOVIR 1691 00:58:43,533 --> 00:58:45,034 AND -- TO TREAT HEPATITIS D, THE 1692 00:58:45,034 --> 00:58:47,337 D MIGHT BE EXACERBATED. 1693 00:58:47,337 --> 00:58:50,406 BUT WE DON'T WANT THEM TO HAVE 1694 00:58:50,406 --> 00:58:51,541 FLARES WHEN THE D GETS 1695 00:58:51,541 --> 00:58:52,442 SUPPRESSED. 1696 00:58:52,442 --> 00:58:53,443 IT'S A REAL ISSUE. 1697 00:58:53,443 --> 00:58:54,844 >> THAT SHOULD HELP US 1698 00:58:54,844 --> 00:58:57,580 UNDERSTAND THE MECHANISMS OF 1699 00:58:57,580 --> 00:59:00,049 INFECTION CONTROL, BUT HAVE WE 1700 00:59:00,049 --> 00:59:01,150 LEARNED ANYTHING FOR WHAT'S 1701 00:59:01,150 --> 00:59:03,119 GOING ON WHEN THAT ACTIVATION 1702 00:59:03,119 --> 00:59:09,259 OCCURS? 1703 00:59:09,259 --> 00:59:13,229 >> SO WITH COINFECTION -- 1704 00:59:13,229 --> 00:59:15,965 USUALLY IT IS -- HEPATITIS C, B 1705 00:59:15,965 --> 00:59:16,499 IS LIKELY LOWER. 1706 00:59:16,499 --> 00:59:18,001 SO THE HYPOTHESIS AND JAKE HAS 1707 00:59:18,001 --> 00:59:20,737 DONE WORK IN HIS LAB ABOUT A LOT 1708 00:59:20,737 --> 00:59:22,038 OF THESE COMPETITION BETWEEN 1709 00:59:22,038 --> 00:59:24,507 HEPATITIS B, IT'S TUESDAY LISH 1710 00:59:24,507 --> 00:59:26,809 BEEN TWO VIRUSES COMPETING FOR 1711 00:59:26,809 --> 00:59:28,878 THE SAME HEPATOCYTE, ONE WINS 1712 00:59:28,878 --> 00:59:30,613 OUT, AND WHEN ONE IS GONE, IT 1713 00:59:30,613 --> 00:59:33,449 OPENS UP ALL THE OTHER OPENINGS 1714 00:59:33,449 --> 00:59:34,517 FOR THE NEW VIRUS THAT'S 1715 00:59:34,517 --> 00:59:36,519 ACTUALLY THERE IF IT'S NOT ON 1716 00:59:36,519 --> 00:59:37,987 TREATMENT, SUPPRESSIVE 1717 00:59:37,987 --> 00:59:39,622 TREATMENT, YOU CAN INVADE AND 1718 00:59:39,622 --> 00:59:41,057 GET A FLARE. 1719 00:59:41,057 --> 00:59:42,158 THAT'S THE COMMON SENSE ANSWER. 1720 00:59:42,158 --> 00:59:44,294 >> SO IT'S NOT A HOST EFFECT, 1721 00:59:44,294 --> 00:59:47,030 IT'S A COMPETITION FOR THE 1722 00:59:47,030 --> 00:59:47,497 HEPATOCYTE. 1723 00:59:47,497 --> 00:59:50,667 AT LEAST THAT'S THE THOUGHT. 1724 00:59:50,667 --> 00:59:53,870 >> AND NOT TO SPEAK FOR YOUR 1725 00:59:53,870 --> 00:59:55,538 WORK, BUT I THINK JAKE ALSO 1726 00:59:55,538 --> 00:59:57,807 SHOWED THERE'S CHANGE IN 1727 00:59:57,807 --> 00:59:59,242 INTERFERON WITH SUPPRESSION OF 1728 00:59:59,242 --> 01:00:01,244 ONE VIRUS ALLOWING THE SECOND 1729 01:00:01,244 --> 01:00:03,112 VIRUS TO FLARE. 1730 01:00:03,112 --> 01:00:04,113 BUT THAT WAS WITH HEPATITIS B 1731 01:00:04,113 --> 01:00:07,283 AND C, I THINK. 1732 01:00:07,283 --> 01:00:08,985 >> I WANT TO THANK BOTH OUR 1733 01:00:08,985 --> 01:00:10,853 SPEAKERS FOR YOUR TALKS. 1734 01:00:10,853 --> 01:00:13,589 I GUESS THE BAD NEWS TO SPRING 1735 01:00:13,589 --> 01:00:15,191 OFF YOUR STORY, CLEARLY YOU GUYS 1736 01:00:15,191 --> 01:00:16,392 DON'T KNOW ENOUGH BECAUSE 1737 01:00:16,392 --> 01:00:17,493 TOMORROW YOU'RE GOING TO GO BACK 1738 01:00:17,493 --> 01:00:19,162 TO YOUR LABORATORIES AND CLINICS 1739 01:00:19,162 --> 01:00:20,096 TO STUDY THIS VERY IMPORTANT 1740 01:00:20,096 --> 01:00:20,596 QUESTION. 1741 01:00:20,596 --> 01:00:21,564 SO THANK YOU VERY MUCH FOR 1742 01:00:21,564 --> 01:00:23,199 SHARING YOUR WORK WITH OUR 1743 01:00:23,199 --> 01:00:24,434 COMMUNITY. 1744 01:00:24,434 --> 01:00:25,134 THANKS, EVERYBODY. 1745 01:00:25,134 --> 01:00:26,336 HAVE A GREAT AFTERNOON, AND IF 1746 01:00:26,336 --> 01:00:27,437 ANYBODY WOULD LIKE TO SPEAK TO 1747 01:00:27,437 --> 01:00:29,472 THE SPEAKERS AFTERWARDS, PLEASE 1748 01:00:29,472 --> 01:00:29,672 DO SO. 1749 01:00:29,672 --> 01:00:30,840 THANK YOU VERY MUCH. 1750 01:00:30,840 --> 01:00:41,017 [APPLAUSE]