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Camden ME

Camden ME. NHOLUA. Hepatitis C in 2016 Recent advances in Evaluation and Treatment October 18, 2016 Bruce W. Henricks, M.D. FACP. Causes of Chronic Liver Disease. Prevalence of Hepatitis C. Worldwide ~ 3% About 170 million are infected with hepatitis C. Prevalence of Hepatitis C.

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Camden ME

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  1. Camden ME

  2. NHOLUA Hepatitis C in 2016 Recent advances in Evaluation and Treatment October 18, 2016 Bruce W. Henricks, M.D. FACP

  3. Causes of Chronic Liver Disease

  4. Prevalence of Hepatitis C • Worldwide ~ 3% • About 170 million are infected with hepatitis C

  5. Prevalence of Hepatitis C • Since the identification of the hepatitis C virus (HCV) in 1989 • The number of HCV cases in the U.S. has fallen 80% • About 2.7 to 3.9 million estimated to be infected in the U.S. • ~1.6% of the population are living with HCV • ~76% + for HCV were born between 1945 and 1965

  6. Prevalence of Hepatitis C • HCV in the U.S. • HCV accounts for • 20% of all acute cases of hepatitis • ~ 30,500 new acute HCV infections in 2014 • 8000-10,000 deaths per year • 75% of those in ages 45 to 64 • The death rate now exceeds that of HIV • 40% of liver transplants (95% will get recurrent HCV) • About 50% infected with HCV are unaware of their diagnosis

  7. Prevalence of Hepatitis C • HCV in the U.S. • About 17% of HCV(+) patients are late diagnoses • Cirrhosis or hepatic decompensation are already present • ~50-60% of the new cases of HCV occur in people with histories of injection drug abuse • HCV rate in those born from 1945 to 1965 • 6 times higher than those born in other years • 2012 CDC guidelines recommend routine screening for individuals born in those 2 decades

  8. Natural history of HCV

  9. A recent Quick Quote • 58 M $5 Million • HCV since his 30’s • Naïve to treatment until March 2016 • Harvoni completed in late July 2016 • U/S based transient elastography suggests F1 • FibroSure supports F2 • s/t his first PCR post-Harvoni 12 weeks later • Is he STD?

  10. Mt. Washington, NH

  11. HCV Characteristics • Hepatitis C • A spherical, enveloped single-stranded RNA virus • Closely related to viruses of • Hepatitis G • Dengue • Yellow fever • HCV can produce 10 trillion new viral particles each day • Worsened by daily alcohol consumption

  12. HCV Genotypes • HCV has • 6 genotypes, with numerous subtypes • Genotype 1 the major form worldwide, 40-80% of all HCV • Genotype 1a and 1b occurs in3/4s of U.S. cases • Genotypes 2a, 2b, 2c occur in (10-15%) of U.S. cases • Genotypes 3a and 3b in (4-6% of cases) • Most prevalent in India, Pakistan, SE Asia, and Scotland • Genotypes 4, 5, and 6 < 5% of U.S. cases

  13. Transmission of HCV • Those at highest risk • Injection illegal drug users • In developed countries, ~ 60% of Hep C is related to IV drug abuse • Shared straw, cocaine snorting • Less than 20% of new cases through sexual exposure • Other exposures of lower HCV risk • Needle-stick injuries- about 5 % • Maternal-fetal transmission- less than 5 %

  14. HCV Sources of Infection

  15. HCV Case #1 • 49 F • HCV genotype 1a since the early 1990s • Failed Peginterferon + Riba in 2002 • Had a third liver biopsy in 2009 • Stage 1 minimal fibrosis • FibroSure suggests F2 only • June 2016, has stopped occasional alcohol • Minimal elevation in LFTs • A good candidate for Harvoni Tx • Insurance company reviewing coverage

  16. Transmission of HCV • Other exposures of lower risk, cont. • Via tattooing, sharing razors, acupuncture • Transfusion-associated HCV • Blood pool screened since 1990 • Using polymerase chain reaction (PCR) • 1 case in 230,000 units • Window after infection, to detection • Can be 1 to 2 weeks with PCR Immune response to HCV

  17. Incidence of HCV demographics • In U.S. • HCV more common in minority populations • No gender preponderance • 65% of persons with HCV are 30-49 years • Being infected while younger has a somewhat better prognosis • Infection uncommon in those 20 and younger • Unless IV Drug abuse

  18. HCV Prognosis • Chronic HCV • Likelihood of progression influenced by • The natural h/o HCV in that individual + their environment • Alcohol use • Male sex • Ages 40 to 55 years at time of initial infection • Impact of hepatic toxins (alcohol, meds, environmental exposure, etc) on the liver over time • BMIs > 30 • Concomitant hepatitis, or conditions with iron excess • Immunosuppression, or HIV co-infection

  19. Liver Biopsy

  20. Liver Biopsy • Only reliable way to assess current condition • Still may not be predictive of the future course • The biopsy evaluates the extent of hepatic damage • Two important features (Batt’s –Ludwig scoring) • The severity of inflammation or “Grade” • Expressed on a scale of “0 to 4” • Extent of fibrosis or “Stage” • Expressed on a scale of “0 to 4” • Stage 0 no fibrosis…… to Stage 4 cirrhosis

  21. Liver Biopsy in HCV • Numerous staging and grading scoring systems • Batt’s and Ludwig • Referenced in Swiss Re Life Guide • Knodell Histologic Activity Index Score (HAI) • Referenced in Hannover’s Ascent manual • Numerical score given to degree of inflammation and fibrosis • The higher the score the more severe the inflam./fibrosis • Scores of 4 or less = mild inflammation/fibrosis • Regardless of the system used, when fibrosis >“mild” the prognosis worsens

  22. HCV and hepatic fibrosis • Hepatic fibrosis • Initially thought to be irreversible….. No more • A dynamic process with the potential for significant resolution • Molecular understanding of fibrogenesis and fibrosis regression …. (though difficult to predict rate of progression) • Stages of fibrosis (METAVIR scoring) • F0: normal liver with no fibrosis • F1: portal fibrosis w/o septa • F2: a few septa *** ( =/> F2 considered significant fibrosis) • F3: numerous septa, but w/o cirrhosis • F4: cirrhosis

  23. Fibrotic progression

  24. Noninvasive tests for fibrosis • Serologic and radiologic tests • Used to differentiate significant fibrosis (F2 to F4) from those with no or minimal fibrosis (F0 to F1) • Serologic tests more widely available (U.S.) • All have good ability to differentiate F2 or higher • FibroTest/FibroSure, or newer ActiTest Cost $250 • Hepascore • Fibrospect • AST/platelet ratio (APRI)

  25. Noninvasive tests of fibrosis • Serologic tests • Don’t reliably differentiate the separate stages • F1, vs, F2, or F3, etc • Sensitivity 60-75%, specificity 80-90% • APRI = AST value/ ULN of AST divided by the plt count x 100 • AST of 90 / ULN of 45 = 2/ Plt count (120) x 100 • APRI cutoff of .7 for predicting F2 to F4 • APRI cutoff of 1.0 for predicting cirrhosis

  26. Noninvasive tests of fibrosis • Radiologic • Ultrasound-based transient elastography (UTE) • Magnetic resonance elastography (MRE) • Scans the whole liver, but more expensive • Mechanical excitation principles • Fibrotic tissue differs from healthy liver tissue in the way it responds to excitation by sound waves (waves propagate/move faster in fibrotic tissue) • =/>F2 sensitivity of 70% specificity of 84% • F4 sensitivity of 87% specificity of 91%

  27. Noninvasive tests for fibrosis • Clinical application • Used as substitutes for a liver biopsy • Limitations of a liver biopsy • Invasive, ….and associated with complications • Unwelcomed by pts, and must live with sampling inaccuracies d/t • Small size of biopsy • Discrepancies in tissue interpretation • Often used in combination to evaluate HCV • Serologic test + UTE (more commonly) or MRE • Use depends upon local availability and MD preference

  28. Treatment of Hepatitis C- 2013 0% 18%

  29. Treatment of Acute Hepatitis C • When identified in first 1-6 months of infection • Treat as chronic HCV and use new direct anti-virals • d/t efficacy and oral route of Tx • Pegylated interferon + Ribavirin used previously • In 2013, the treatment of choice • Effective in nearly 90% • Unfortunately, early discovery is quite rare • Since most are asymptomatic or only have vague transient symptoms • Explains the true burden of chronic Hepatitis C

  30. Treatment of Chronic HCV • Main goal- a SVR • Achieve a sustained viral response (SVR) • Defined as an absence of HCV-RNA via PCR at least 3 mo (12 weeks) after discontinuation of therapy • Was 6 months with INF-based therapies • Many clinicians will repeat a PCR at 24 weeks post-Tx • Once at a SVR • 97 to 100% chance of being HCV RNA negative long term and thus a “cure”

  31. NHOLUA November 2013 • Expect antivirals to dominate HCV therapy the next 5 years • Sofosbuvir May 2013 • Simeprevir (FDA review 10-13) • Oral therapy with Ribavirin, 80% response rates • A simple oral regimen that becomes a reality will • Significantly reduce HCV morbidity and mortality

  32. Mt. Willard New Hampshire

  33. Current therapies in HCV • Direct-acting antivirals (DAAs) • Target nonstructural proteins of HCV • Disrupt viral replication and the infection • Advantages • Highly effective where 94-99% will achieve a SVR • Well tolerated • All-oral regimens • Behavior and diet • During Tx complete avoidance of alcohol recommended • Benefit of 2-3 cups of coffee • Lessens mortality/hospitalizations across a spectrum of liver disease

  34. DAAs points of viral attack Sofosbuvir Ledipasvir

  35. Current therapies in HCV • Preferred regimens used for 12 weeks • Harvoni (trade name) • Ledipasvir + sofosbuvir in a single pill/ day, $94,500 • May be used just (8 weeks) in • Naïve patient w/o cirrhosis and viral load of < 6 million itnl units/ ml • Epclusa • Sofosbuvir + velpatasvir 1 pill/day, $74,760 • Both used across genotypes, F scores, and h/o Tx

  36. Current therapies in HCV • Other first line regimens used for 12 weeks • Zepatier • Elbasvir + grazoprevir 1 pill/ day $54,600 • Viekira Pak (4 drug combination) • Ombitasvir + paritaprevier + ritonavir + dasabuvir (with or w/o ribavirin) 2 pills/day $83, 319 • 2 drug combos • Simeprevir + sofosbuvir • Daclatasvir + sofosbuvir

  37. Current therapies in HCV • Regimen selected depends upon • Genotype 1a, 1b, 2 etc • Degree of fibrosis • No cirrhosis vs. cirrhosis present or F<2 vs =/> F2 • Treatment status • Naïve (never treated before) • Failed prior treatment (treatment experienced) • Peginterferon + ribavirin (standard of care to 2013) • Sofosbuvir + ribavirin ( 2013 for genotypes 2 and 3)

  38. Current therapies in HCV • Priority patients • Those with • Advanced fibrosis, (= to or > F2) • Liver transplant recipients • Severe extra-hepatic manifestations of HCV infection • Renal • Hematological • Diabetes and HCV • Literally dozens of treatment choices for DAA algorithms s/t the characteristics of each HCV case and its characteristics • Genotype, h/o Tx, fibrosis present etc.

  39. Current therapies in HCV • Preferred regimens used for 12 weeks • Harvoni (trade name) • Ledipasvir + sofosbuvir in a single pill/ day, $94,500 • Epclusa • Sofosbuvir + velpatasvir 1 pill/day, $74,760 • Harvoni and Epclusa used across • All genotypes • F scores • Treatment naïve or experienced

  40. Underwriting Hepatitis C • Recognize that degrees of fibrosis have the potential to resolve • Accept we will won’t see as many liver biopsies as we’d like • Noninvasive substitutes will very likely increase • Serologic and radiologic tests • FibroSure, FibroSpect, ActiSure …….etc • U/S-based transient elastography • Value of knowing < F2 vs > F2

  41. Underwriting Hepatitis C • Hep C cases with DAAs are here now • Harvoni and Epclusa will be popular • d/t their efficacy and being once daily • 94-99% will achieve a SVR • Other DAAs and regimens will evolve and be used • Availability to receive DAAs varies and should improve

  42. HCV case # 1 • 49 F candidate for Harvoni • Treatment ends in mid-October • If we had to rate now? • Jump to January 2017 and PCR negative for HCV • Chance of a SVR? • Is she STD at that time? • What HCV attributes does she have?

  43. Underwriting Hepatitis C • Only about 1 in 10 candidates for DAAs receive them at present • Cost of a liver transplant $330,000 to $577,000 • Negotiated price with insurance $120,000 • DAAs gaining acceptance • Reinsurers vary on HCV after treatment • Hannover Life Re appears most current

  44. Quick Quote • 58M $5M • HCV since his 30’s • FibroSure suggests F2, UTE supports F1 • Harvoni Tx ended in late July of this year • s/t his first PCR post-Harvoni in late October • Could he be STD? • Would you want another PCR at 24 weeks post-Tx?

  45. Crawford depot, NH

  46. Hepatitis C in 2016 Questions?

  47. Resources • eMedicine.com: Hepatitis C, March 2016 • Up to Date August 2016 • NIH.gov Hepatitis C: a clinical review • Swiss Re Life Guide • Hannover Re Ascent • Liang TJ, Ghany MG. Current and Future Therapies for Hepatitis C Virus Infection: NEJM 2013; 368; 1907-17 • Jacobseon IM, Gordon SC, Dowdley KV et al. Sofosbuvir for Hepatitis C genotype 2 and 3 in Patients without Treatment Options. NEJM 2013;368; 1867-77

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