1. ROBERT RUDAS, M.D., AAHIVS HIV / HEP C PROVIDER, MULE CREEK STATE PRISON

2. Inmate populations bear a disproportionate share of hepatitis c virus infection  16-41 % of prisoners in the US had evidence of exposure to HCV, compared to 1.6% of the general population.  MULE CREEK STATE PRISON – 29% HCV Ab +  1 in every 3 persons with HCV infection in US has passed through jail or prison over the course of a year.

3. TREATMENT IN THE CORRECTIONAL SETTING IS COST EFFECTIVE  Traditional therapy with Pegylated Interferon & Ribavirin has been cost effective with cost per “quality adjusted life-years” gained

4. SUDDENLY A NEW DYNAMIC EMERGES 2 New direct-acting antivirals (DAAs), BOCEPREVIR & TELAPREVIR  More effective and can treat some patients for shorter duration of time  BUT! Increases the cost of treatment from $25,000 (for Peg/Riba alone) to $50,000 - $75,000 for these new 3-drug regimens

5. TWO-THIRDS OF THOSE LIVING WITH HCV WERE BORN BETWEEN 1945 & 1965 HOW DOES THIS IMPACT CORRECTIONAL TREATMENT COSTS? THE GOOD NEWS: As the birth cohort ages out of crime-prone years (approximately 20-45 years of age), prisons would be expected to bear a declining share of the epidemic. THE BAD NEWS: The cost burden correctional institutions will have to carry in the next 10-15 years is going to astronomical!

6. ETHICALLY, CORRECTIONAL HCV TREATMENT PROVIDES:  Unquestionable increased live span and improved quality of life for the patient  Huge contribution to the health of the prison inmates  Big contribution to the community for inmates that parole

7. OH BY THE WAY……… Don’t forget about the millions, if not billions, of dollars that will be saved from the onslaught of Baby Boomers that will require repeated hospitalizations for their end-stage liver disease (ESLD) if they are not treated.

8. THE HCV RNA VIRUS

9. HCV GENOTYPE BREAKDOWN IN THE US:  Genotype 1 - 70%, most difficult to treat  Genotype 2 – 16%, easier to treat  Genotype 3 – 12%, easier to treat  Genotype 4 - 1%, moderately difficult to treat  Genotypes 5 & 6 – Very rare in the US. (mostly in Africa & Asia)

10. HOW IS HCV CONTRACTED?

11. ONE OF THE MOST PREVALENT VECTORS IN THE PRISON POPULATION

12. HOW IS HCV CONTRACTED? SEXUAL CONTACT:  Men having sex with men (MSM) – 3-4%  Male-Female intercourse - <1%

13. HOW IS HCV CONTRACTED? Blood Transfusions : Since 1992 all transfused blood is tested for HCV, but before 1992 blood transfusions was one of the leading causes of HCV transmission.

14. NORMAL LIVER HISTOLOLGY

19. CIRRHOSIS

20. CIRRHOSIS / FIBROSIS STAGING

24. CIRRHOSIS / HCV / HCC  20 % OF PATIENTS WITH HCV DEVELOP CIRRHOSIS  20% OF PATIENTS WITH CIRRHOSIS DEVELOP HEPATOCELLUAR CA

25. BREAKDOWN ON CIRRHOSIS  COMPENSATED CIRRHOSIS  DECOMPENSATED CIRRHOSIS

26. DECOMPENSATED CIRRHOSIS ASCITES

27. HEPATIC ENCEPHALOPATHY

28. ESOPHOGEAL VARICIES WITH HEMORRAGE

29. DECOMPENSATED CIRRHOSIS  SPONTANEOUS BACTERIAL PERITONITIS  HEPATORENAL SYNDROME  HEPATOPULMONARY DISEASE  CHILD-PUGH SCORE >/= to 7 (>/= TO 6 if HIV+)

30. CHILD-PUGH SCORE CALCULATION

31. DECOMPENSATED CIRRHOSIS HEPATOCELLULAR CARCINOMA

32. APPROACH TO HEP C TREATMENT  WHO TO TEST  WHO TO TREAT  WHO NOT TO TREAT

33. WHO TO TEST ?  High risk behavior eg. MSM, IVDU, Tattoos.  EVERYONE born between 1945 & 1965. This “baby boomer” cohort has a 5 times greater risk of having contracted HCV than the rest of the population.  Any suspicious acute elevation in AST/ALT on a routine chemistry panel.  ALL incarcerated persons ?

34. WHO TO TREAT? All GENOTYPE 1 patients with :  Stage 3 or > fibrosis liver biopsy in the past 5 years if HIV negative.  Stage 2 or > fibrosis in the past 3 years if HIV+.  This is whether they are treatment naïve or whether they have failed a failed an Interferon/Ribavirin regimen in the past.  Need for an adequate depth biopsy – ideal 2.5 cm.

35. WHO TO TREAT?  All treatment naïve patients with GENOTYPE 2 & 3 with NO BIOPSY required.  All treatment naïve patients with GENOTYPE 4, 5, & 6 with a liver biopsy of Stage 2 or greater.

36. WHO NOT TO TREAT ?  MUST NOT HAVE:  Poorly controlled cardiopulmonary disease, cerebrovascular disease, thyroid disease, blood dyscrasias, seizures, cancer, renal insufficiency (Cr >2, Cr Cl<50), or uncontrolled Diabetes (Hgb A1C.8.5)  HIV infection with CD4<200  Hx kidney, lung, or heart transplant  Autoimmune disease  Ongoing illicit drug or alcohol use  WBC < 1,500  Platelet count < 75,000 (of which many cirrhotics have)

37. WHO NOT TO TREAT ? MUST NOT HAVE:  Hemolytic anemia  Hgb < 11  Hct < 33  Allergy to Interferon or Ribavirin  Pregnancy  Inability to practice contraception  History of decompensated cirrhosis  Hepatocellular CA  Inability to cooperate with treatment

38. WHO NOT TO TREAT ? MUST NOT HAVE:  Inability to give informed consent  Poorly controlled depression  Suicidal behavior in the past 12 months  Genotypes 2,3,4,5,or 6 that have not responded to prior Peg/Riba treatment  Parole dates of <16 months if genotype 1, 4, 5, 6 or parole date <8 months if genotype 2 or 3.

39. GOAL OF HCV TREATMENT To have a non-detectable HCV viral load 6 months after the completion of the treatment regimen = “CURE”

40. CURRENT TREATMENT REGIMENS  PEGINTERFERON 2 ALPHA WITH RIBAVIRIN (genotype 2, 3, 4, 5, 6)  BOCEPREVIR PROTOCOL WITH PEG/RIBA (genotype 1 only)  TELAPREVIR PROTOCOL WITH PEG/RIBA (genotype 1 only)

41. PEGINTERFERON 2 ALPHA  Alpha Interferons used since 1980 to treat Hep C.  Still backbone of HCV treatment.  Pegylated interferon was introduced in Jan 2001 (covalent bond with Polyethylene glycol, giving it a longer duration of action).  Clinically proven antiviral activity against HCV, but exact mechanism is not known.  When given with Ribavirin yields 30-55% success with genotype 1, 60-70% success with genotype 2 & 3.  Started at a dose of 180mcg/week and lowered to 135mcg/week if drug induced neutropenia or thrombocytopenia.  Causes a plethora of side effects.

42. PEGINTERFERON SIDE EFFECTS  Fever, chills, headache myalgia, fatigue, nausea, anorexia  Psychiatric side effects of depression, irritability, anxiety, insomnia, confusion, difficulty concentration and memory.  While less common also: aggressive behavior, psychosis, hallucinations,and even suicidal behavior.  Hematologic side effects of neutropenia & thrombocytopenia.  Additional side effects of colitis, pancreatitis, retinopathy (to include blindness), hair loss and injection site reactions.

43. RIBAVIRIN  A nucleoside inhibitor that will not treat Hepatitis unless it is given with interferon.  Clinically proven to increase the efficacy of interferon  For genotypes 2 & 3 is given at a standard dose of 400mg bid  For genotypes 1, 4, 5, 6 is given on a weight base dosage  Is teratogenic  Contraindicated if Creat > 2 or Cr Cl > 50.  Primary side effect is hemolytic anemia, and dosage is decreased if Hgb drops to < 10.

44. PEGYLATED INGTERFERON / RIBAVIRIN (Peg Riba) TREATMENT RULES: Genotype 2 or 3 / HIV negative: 24 weeks Peg/Riba 400mg bid. Genotype 2 or 3 / HIV positive: 48 weeks Peg/Riba 400mg bid. Genotype 4,5,6 – 48 weeks Peg and weight based Riba. FUTILITY RULES: Genotype 2 or 3 – HIV neg: Week 12, any detectable viral load------- -------STOP TX Genotype 2 or 3 – HIV pos: Week 12, < 2 log decrease in viral load--- ------STOP TX Genotype 4,5,6: Week 12, < 2 log decrease in viral load----------------- ------STOP TX Genotype 2,3,4,5,6: Week 24, any detectable viral load----------------- ------STOP TX

45. BOCEPREVIR  Protease inhibitor / Direct Acting Antiviral (DAA) agent  Approved by the FDA in 2011  For treatment of genotype 1 only  Dramatically increase cure rate (75% compared to 30- 45% with Peg/Riba)  Duration of treatment is based on viral load response – “Viral Response Guided Therapy”  Need to give 4 pills (total 800mg) exactly every 8 hours with fatty content meal in the stomach  Side effects include: Anemia, neutopenia, dysgeusia (alteration in taste), dry mouth, nausea, vomiting & diarrhea

46. BOCPREVIR TREATMENT PROTOCOL

47. TELAPREVIR  Also a protease inhibitor / DAA  Approved by FDA in 2011  Included in the CDCR Formulary in 2012  Successful cure rate parallels Boceprevir at about 75%  Also given with “Viral Response Guided Therapy”  Need to give 2 pills (total 750mg) every 8 hours with fatty meal in stomach  Side effects include: Rash, especially a burning anorectal pruritis in 11% of patients; serrious skin reactions like DRESS and Steven-Johnson, and anemia.  Less drug interactions with HIV meds c/w Boceprevir

48. TELAPREVIR TREATMENT PROTOCOL

49. RESISTANCE MUTATIONS WITH BOEPREVIR & TELAPREVIR  100% cross-resistance with Boceprevir and Telaprevir  No logic to switch between the 2 agents for management of treatment failure

50. NEW DAA AGENTS IN THE PIPELINE  Next-generation protease inhibitors  Nonstructural protein (NS5A) inhibitors  Nonnucleoside polymerase inhibitors  Nucelos(t)ide polymerase inhibitors  Interferon alpha “free” regimens  Recent trials yielding 90% cure rates!

51. AGENTS YOU WILL SEE IN THE NEXT YEAR SOFOSBUVIR  Nuceloside polymerase inhibitor  To be approved for NON-interferon tx of genotypes 2 & 3  Very low side effect profile  May be approved by FDA in December 2013 DACLATASVIR  Completely different mechanism (NS5A Inhibitor)  No cross resistance with protease or polymerase inhibitors

52. PARALLELS IN THE DEVELOPMENT OF HEPATITIS C TREATMENT WITH THE HISTORY OF HIV TREATMENT