HCV: FROM HIPPOCRATES TO CURE:

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1 HCV: FROM HIPPOCRATES TO CURE: A 2000 YEAR RETROSPECTIVE Harvey J. Alter, MD, MACP Department of Transfusion Medicine NIH

2 THE SOMMER SEASONS EARLY SOMMER Discovery of HBV Discovery of NANB/HCV Eradication of post-transfusion hepatitis Emergence of arthropod-borne (TTIs) Getting to zero TTIs Pathogen reduction MID-SOMMER HCV: Prevalence & Transmission HCV: Mechanisms of persistence HCV: Clinical Outcomes HCV: Treatment and Eradication LATE SOMMER HEV

3 FINANCIAL DISCLOSURE People who work at NIH only dream about having financial disclosures Wait, this just in. NIH has just prohibited dreaming

4 CRITICAL NON-FINANCIAL DISCLOSURES My guiding scientific principle is that to steal from one is plagiarism.. but to steal from many is research Nothing I say reflects the position of the US government ---- which instantly gives it great credibility and relevance My memory is not as sharp as it used to be And also, my memory is not as sharp as it used to be

5 TIMELINE OF HEPATITIS HISTORY First to Describe: Ikterus Kirros Campaign jaundice Vaccine jaundice Hep A vs. Hep B 2000 YEARS BC THE OATH Physician, first, do no harm Physician, second, get paid upfront and do not take Medicare 1960 s

6 HEPATITIS B: THE INFANT YEARS Baruch S. Blumberg, Harvey J. Alter, Sam Visnich JAMA 1965;191:541

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11 THE DANE PARTICLE: HBV VIRION

12 A RANDOMIZED CONTROLLED TRIAL OF HBV VACCINE IN 1083 HOMOSEXUAL MEN >95% of immunized subjects developed protective anti-hbs Vaccine-induced antibody persisted >24 months Hepatitis attack rate was 3.2% in vaccine recipients versus 25.6% in controls (p<0.0001) In those who received all 3 doses of vaccine, protective efficacy approached 100%

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15 I ALWAYS GIVE 100% AT WORK 12% on Monday 23% on Tuesday 37% on Wednesday 23% on Thursday 5% on Friday

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17 Post-Transfusion Hepatitis at NIH-1

18 Post-Transfusion Hepatitis at NIH-2

19 Post-Transfusion Hepatitis at NIH-3 Transmitted From Patients with acute and chronic NANB hepatitis Asymptomatic implicated donors

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24 UNRESOLVED ISSUE Is NANB hepatitis clinically significant?

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26 QUESTIONS EVEN MORE IMPONDERABLE THAN THE MEANING OF NON-A, NON-B If a man speaks in the forest and a woman is not there to hear him Is he still wrong? Do infants have as much fun in infancy.. As adults do in adultery?

27 Post-Transfusion Hepatitis at NIH-4

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29 A POEM OF FRUSTRATION I Can t See The Forest For The HB Ags

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31 There Is No Sense Chiron Over Spilt Milk

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33 Post-Transfusion Hepatitis at NIH-5 Estimated that in US, transfusion may have transmitted: 4.8 million HCV infections from HCV testing prevented 2.4 million transmissions from

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36 Bacteria In RT stored Leukocytes platelets GVH and transfusion Emerging/Unknown reactions Viruses Known Pathogens False Negatives For which no Limits of detection assay is mandated of current assays (e.g., windowperiod issue)

37 CHIK ZIKA

38 Any agent capable of causing disease in man that has an asymptomatic viremic phase is a threat to be transfusion-transmitted. The likelihood of that transmission is highly dependent on the duration of viremia and the level of concern is dependent upon the severity of the ensuing disease. Unscreened Threats Future Threat to Blood Supply vcjd HAV Malaria sp. HEV HHV-8 HPV Dengue (Other Arbov) Parvo-B-19 B. Microti (Babesia) Rickettsia (Q-Fever) B. Burgdorferi (Lyme) Chikengunya The next really bad one (HIV-X)

39 THE PRECAUTIONARY PRINCIPLE For situations of scientific uncertainty, the possibility of risk should be taken into account in the absence of proof to the contrary Corollary: The precautionary principle asserts that measures need to be taken to face potential serious risks Alter Corollary: Pathogen reduction is the ultimate precautionary principle by eradicating almost all potential for infectious disease transmission even before risk has been conclusively established, and possibly, even before the agent has been recognized

40 Amotosalen HCl (S-59) Mechanism of Action UVA Illumination Amotosalen HCl (S-59) DNA or RNA of pathogen Docking CONFIDENTIAL Permanent Crosslinking

41 S-303 Mechanism of Action Linker Amustaline Effector Unreactive S-303 by-product Physiologic ph DNA or RNA of pathogen Acridine Anchor Docking CONFIDENTIAL Permanent Crosslinking

42 ADVANTAGES OF PATHOGEN REDUCTION Effectively inactivates most clinically relevant viruses whether RNA or DNA, ss or ds, enveloped or non-enveloped, intra-cellular or extra-cellular Inactivates virtually all clinically relevant gm.+ and gm.- bacteria Inactivates all the spirochetes, rickettsia and protozoa of known transfusion relevance Prevents transfusion associated GVH Offers probable preemptive protection against pathogenic, potentially lethal, agents that will inevitably emerge in the future

43 IMPEDIMENTS TO PATHOGEN REDUCTION Decreased platelet yield (10-30%) observed in clinical trials Insufficient kill of some hi-titer agents (HAV, Parvo B-19) Toxicity: None known for riboflavin; theoretical risk for psoralens, but the residual doses transfused are very low; very wide safety margin Currently, no licensed method for whole blood or PRC negating some of the advantages that would accrue with a comprehensive single process for all blood products Cost: High; main impediment to implementation

44 Perceptions and Realities Perception: Everyone wants safer, better blood Reality: No one wants to take a risk or incur the cost of new approaches to achieve this in the absence of either a crisis or a major push by the healthcare community or public at large Perception can become reality only if costs are low Ray Goodrich ; Caridian BCT

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47 IN CONCLUSION, I AGREE WITH EVERYTHING I HAVE SAID

48 A WORD OF WISDOM GARNERED OVER 50 YEARS OF RESEARCH EXPERIENCE Before you criticize competing scientists, you should walk a mile in their shoes That way, when they respond negatively, or even viciously, you are a mile away and you have their shoes

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52 Combination Sofosbuvir (NS5b) and Velpatasvir (NS5a) for Treatment of HCV Genotype 1-6 Infections Study First Genotypes Studied Treatment Cirrh. No. Prior Comp. SVR-12 Author Astral-1 Feld, J 1,2,4,5, % 19% 99%* 6 CI: 98- >99 Astral-2 Foster, G % 14% 99% CI: Astral -3 Foster, G % 29% 95%** CI: Astral-4 (Curry): 83% (CI: 74-90) SVR-12 in 267 with decompensated cirrhosis * 2/624 (0.3%) relapsed; ** 11/277 (4%) relapsed NEJM 2015;373:

53 HCV Life Cycle and DAA Targets Receptor binding and endocytosis Transport and release Fusion and uncoating ER lumen (+) RNA Virion LD assembly LD Translation and LD NS3/4 protease Membranous polyprotein inhibitors web NS5B RNA polymerase replication inhibitors processing ER lumen Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:

54 Hepatitis C: Paradoxes & Economics Although efficacy of new treatments will be high, more than half of HCV carriers remain unidentified and, even if identified, many do not receive proper therapy; greatly magnified in developing nations Because of high global HCV prevalence, the absolute number of potential HCV-related dire events is staggering, even if the proportion who suffer these events is relatively small The cost of treating 3.2 million is 270 billion, roughly 10% of the total US health care budget; 50-fold higher if include the 150 million infected globally unless price adjusted

55 Could HCV be treated to eradication even in the absence of primary prevention with vaccine? The answer is yes but the limitations are the need for: 1) detection of almost all carriers through massive screening 2) marked reduction in drug pricing 3) global delivery of DAAs with >90% penetration in each population.

56 HEPATITIS C: THE PARADOX Although efficacy of new treatments is very high, more than half of HCV carriers remain unidentified and, even if identified, many do not receive proper therapy; this is greatly magnified in developing nations Because of high global HCV prevalence, the absolute number of potential HCV-related dire events is staggering, even if the proportion who suffer these events is relatively small

57 PROTECTIVE BARRIERS AGAINST TRANSMISSION OF PATHOGENS Donor Testing Selection/Exclusion Inactivation Removal

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59 REMARKABLE ACHIEVEMENTS OVER FIVE DECADES OF HEPATITIS VIRUS RESEARCH Identification of HBV, HAV, HDV, HEV, NANB/HCV Established strong link between HBV, HDV, HCV and hepatocellular carcinoma Development of vaccines for HBV, HAV and HEV The virtual eradication of post-transfusion hepatitis Successful transplantation for HCC & end-stage LD Highly effective long-term suppression of HBV replication with oral nucleos(t)ide inhibitors Greater than 95% cure rates in chronic hepatitis C using oral direct acting anti-virals Is it possible, or even likely, that hepatitis B & C can be eradicated over the next 3-5 decades?

60 A PHILOSOPHIC PERSEPECTIVE OF LIFE VERSUS AGE G I V E A D A M N ME AGE

61 Testing versus Inactivation unknown viruses all products leukocytes no additives broad range of pathogens Testing Inactivation no method for all products yet unknown viruses not effective against all pathogens restricted range of pathogens (e.g. spec.viruses (only some methods); costs dependent on number of prions; bacterial spores) pathogens tested increasing process costs Institute for Transfusion Medicine and Immunohematology Johann Wolfgang Goethe University Clinics Frankfurt / Main, Germany German Red Cross Blood Donor Service Baden-Wuerttemberg Hessen

62 Bloodborne Pathogens Platforms V2: DNA Viruses, V3: RNA and DNA Viruses, Version 1: RNA Viruses Bacteria, Protozoa Bacteria, and Protozoa N=10 N=14 N=24

63 ZIKAV WNV 79 ZIKAV Specific Probes 211 WNV Specific Probes WT=Old Kit (Agilent) OVT= New kit (Nugen) CP=virus copy number

64 INTERCEPT Blood System for Platelets Platelets (65% InterSol / 35% Plasma) INTERCEPT Illuminator CONFIDENTIAL

65 RISK MODELS: NAT YIELD VS. IR-WP Virus No. Units No. Risk Risk Screened Cases (MP-NAT (IR-WP) Yield) HCV 37.5x in 1.5x in 1.6x10 6 HIV 36.7x in 1.7x in 1.8x10 6 HBV 1.4x in 174,000 1 in 269,000 Busch, M. Transfusion 2006;46:

66 OFFSETS TO COST FOR PATHOGEN REDUCTION Platelet & Plasma PR Only Eliminate bacterial testing Eliminate product irradiation Extend platelet shelf life to 7 days Whole unit or all-component PR Eliminate some current assays (RPR, anti-hbc, Chagas,?WNV,?HTLV 1,2) Preempt future testing (HHV-8, babesia, CHIK, dengue, Zika, malaria, HEV, agent du jour) Allow for continued and safer mini-pool testing Reduce donor exclusions based on geography (malaria, ZIKA)

67 DONOR TESTING FOR INFECTIOUS DISEASE IN U.S. HBV NAT WNV Chagas Babesia Dengue Chik Zika HEV HIV HCV NAT HIV Ag Anti-HCV Anti-HTLV vcjd ALT Malaria Anti-HBc HHV8 Leishmania Anti-CMV Foamy viruses Anti-HIV LCT HBsAg Ebola Syphilis Bird Flu