1. VIRAL HEPATITIS & CO-INFECTION James Hand Clinical Nurse Manager for HIV & Hepatitis Research Barts Health NHS Trust

3. The cause of liver disease Hepatotoxic antiretroviral drugs? Substance misuse (Alcohol/rec drugs) Fatty Liver Disease? Hepatitis co-infection?

4. What does the liver do? Produces bile Breaking down food to create and store energy Stores vitamins and minerals including iron Breaks down and eliminates toxins Produces hormones and proteins for most of the chemical reactions in the body such as clotting

7. Hepatotoxicity of ARVs Early ARVs cause hepato-toxicity Nevirapine – acute liver failure (+/- rash) Ritonavir – low dose less of a problem D4T – lactic acidosis but little use anyway DDI – non cirrhotic portal hypertension Darunavir, Tipranavir – case reports of toxicity although rare Drugs used for opportunistic infections Benhamou Y Hepatology 2001 John M AIDS 1998 Labarga P CID 2007

8. Alcohol & liver disease is well documented Alcoholic liver disease is the commonest form of cirrhosis in the western world Non-Alcoholic Fatty Liver Disease Increasing waistlines Insulin resistance More common in men Prevalence increasing

9. The cause of liver disease Hepatotoxic antiretroviral drugs? Substance Misuse (Alcohol) Fatty Liver Disease? Hepatitis Co-infection?

10. What is Hepatitis? ‘Hepa’ = Liver ‘titis’ = inflammation Caused by several agents – Toxins – Drugs – Alcohol – Obesity – Viruses

11. HEPATITIS B CO-INFECTION

12. Hepatitis B (HBV) = DNA VIRUS Approx 350 million people worldwide (WHO) 50 to 100 times more infective than HIV Able to survive outside the body for up to 7 days Controllable & Preventable Very effective vaccine 12

13. Not directly damaging to the liver despite millions of virons being produced daily. Immune response to infection causes inflammation and scaring (Fibrosis) Build up of fibrosis over time leads to cirrhosis and also hepatocellular carcinoma (HCC) If initial immune response does not clear the virus, repeated episodes of inflammation once the virus enters the ‘chronic stage’ is the main cause of the damage

14. Vertical transmission results in an increased rate of chronic infection (95% of children progress to chronic) HBV caught in adulthood – Higher chance of ‘self- clearing’ (approx. 80%) HIV co-infection reduces the chance of clearing to nearer 60% - increasing the prevalence of chronic HBV transmitted in adulthood.

15. Transmission Routes All body fluids Vertical transmission Contaminated medical equipment IV Drug use Sexual exposure

16. HBV/HIV Up to 20% of HIV infected individuals have evidence of current or past infection with HBV HBV does not affect natural history of HIV or the associated treatment response However HIV does have an impact on HBV infection by worsening the prognosis of HBV Increased risk of cirrhosis/ESLD Increased risk of death

18. Why cant we cure HBV? Latent, non-replicating viral genomes Persist within reservoirs for each of these infections, and high levels of viral replication typically resume soon after cessation of antiviral therapy, even after years of treatment 18

19. Serology of hepatitis B Anti HBc – Hepatitis B core antibody HBsAg – Hepatitis B Surface Anitgen Anti HBs- Hepatitis B Surface Antibody HBeAg – envelope antigen indicating high infectivity and replication Anti-HBe – envelope antibody indicative of low replication HBV DNA (viral load) actively replicating virus

20. Vaccinating HIV+ Patients Can delay vaccination till CD4 >200 25% response with CD4 < 200 80% response with CD4 >500 » Balance of risks » Course can be repeated for non-responders with double dose Non responders Annual markers for HBV infection Check markers again before starting ARVs Educate on exposure risks

21. Evaluation of the HIV co-infected patient HIV status CD4 count/ARVs HBV status eAg, HBV DNA Liver status ALT (AST),Albumin, INR, AFP, scan, biopsy Other infections HAV status (vaccinate) Life style Infection risks (vaccinate contacts), Alcohol abstinence

22. Treatment of chronic HBV Treatment in HBV infection aims: – Suppress Viral replication – Reduces inflammation – Prevent fibrosis progressions – Prevent development of Cirrhosis

23. When to treat? HBV DNA > 2000 Evidence of Fibrosis CD4 < 500

24. Treatment of chronic HBV Treatment with Tenofovir/FTC as part of HIV regimen is gold standard 3TC is effective but risk of developing resistance is higher It is important to maintain anti-HBV properties if switching ARV’s. Consider Entecavir if unable to use Tenofovir. 24

26. HEPATITIS C CO-INFECTION

27. Hepatitis C (HCV) = RNA VIRUS Worldwide prevalence of Approx 150million Able to survive outside the body for up to 3 weeks Ongoing improvements in treatment options Can be ‘cured’ 27

28. Only approx. 20% clear the virus spontaneously Chronic hepatitis C can remain asymptomatic for 30+yrs Prevalence higher than 50% in IVDU’s in Europe Adequate treatment can clear the virus fully – no DNA integration or viral reserve

29. Virology of HCV First identified in 1989 Prior to that known as non A non B Hepatitis A small (50nm) enveloped single stranded RNA virus Replicates within the hepatocytes of the liver but also found in most other organs 6 major genotypes (1-6) with subtypes Initial infection often asymptomatic Antibodies provide no protection against re- infection and there is no vaccine

30. Transmission Routes Drug use Blood Transfusions Vertical Transmission High Risk sexual activity (MSM) Contaminated medical equipment

31. Signs & Symptoms Majority report little or no symptoms of early infection If any symptoms are present, usually non specific e.g. lethargy, nausea, muscle aches & pains Rarely jaundice Raised Alanine Transaminase (ALT) or transaminitis due to immune response High ALT often sign of likely self clearance

32. Diagnosis & Serology Diagnostic bloods Raised ALT HCV Ab HCV PCR (viral load) General rule ALT 2.5 >normal ?HCV Detectable by viral load within 1 – 3 weeks Detectable by Antibody can take up to 24 weeks

33. HCV/HIV Approx 25% of HIV+ patients are infected with HCV worldwide EuroSIDA 33.9% Southern Europe nearly 50% US 16% - 25% Increasing incidence of acute HCV infection in young men (MSM) Interactions between Viruses

34. Effect of HCV on HIV Controversial Swiss cohort – some effect HCV increases AIDS/death Failure to increase CD4 with ARVs No effect on HIV VL suppression EUROSIDA – no effect on HIV disease However – data in studies is often difficult to interperate: HCV acquired first in studies Now more likely to be caught later Law et al AIDS 2004 Stebbing J. CID 2005 Sullivan P. AIDS 2006

35. Effect of HIV on HCV Definitely accelerates progress: Median time to cirrhosis 23 v 32 years Higher HCV viraemia in co infected Clifford G. AIDS 2008 Mohsen A. Gut 2003 Smit C. AIDS 2006

36. What does progression look like?

37. Stages of fibrosis

38. Treatment options

39. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. SVR (%) IFN 6 mos PegIFN/ RBV IFN 12 mos IFN/RBV 12 mos PegIFN 12 mos 2001 1998 2011 Standard IFN RBV PegIFN 1991 DAAs Peg/RBV /DAA IFN/RBV 6 mos 6 16 34 42 39 55 70+ 0 20 40 60 80 100 DAA’s 90+ 2014 The Good News

40. Traditional Therapies Pegylated interferon & Ribivirin Low Cure Rates Side Effects Toxicity Management

41. Therapy ‘response guided’ – Null responders – Partial responders – Relapsers High drop-out rate due to side effects Different genotypes have different cure rates

42. Managing Side Effects Pegylated Interferon Lowers Hb Fatigue Neutropenia Flu-like symptoms Depression Psychosis Lowers Platelets Weight Loss Ribivirin Lowers Hb Flu-like symptoms Rash

43. Fatigue Management Check Bloods regularly and dose reduce drug Encourage small regular exercise Flu-like Symptoms Regular Paracetamol Dose Interferon at Night Rash Emollients! Anti-histimines

44. Anxiety/Depression Psychiatry input Anti-depressants (watch for interactions) Counselling Ultimately its about encouraging patients to Continue on therapy for as long as possible

45. HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside Block replication complex formation, assembly NS5A inhibitors RNA replication

46. So what does this mean? Different classes of drugs developed Protease Inhibitors NS5B Polymerase inhibitors NS5A Replication Assembly Complex inhibitors

47. A Major Advance: The first PI’s for Hep C 0 20 40 60 80 100 SVR (%) PegIFN/RBV BOC or TVR + PegIFN/RBV 38-44 63-75 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM et al. N Engl J Med. 2011;364:2405-2416.

48. No Free Lunch

49. Upcoming Agents Polymerase Inhibitors – Sofosbuvir – ABT-072 – ABT-333 – BMS-791325 CypA Inhibitors – Alisporivir PIs - Simeprevir - Faldaprevir - Asunaprevir - ABT-450 - MK5172 - Danoprevir - GS-9451 NS5A inhibitors - Daclatasvir - Ledipasvir - ABT-267

50. How do we decide who to treat now and who can wait? Waiting game?

51. Stage of liver damage Availability of drugs Prior treatment response Cost !!!

52. 96 Example of Nuc Backbone + PI in Trt-Naive Pts and Nulls (COSMOS) SVR12 (%) F0-F2 Fibrosis 100 80 60 40 20 0 96 93 26/ 27 13/ 14 SMV (PI) + SOF (Nuc) + RBV 12 wks SMV (PI) + SOF (Nuc) 12 wks SVR4 (%) F3/F4 Fibrosis 100 26/ 27 14/ 14  78% GT1a  50% Q80K  94% non-CC  All nulls  78% GT1a  40% Q80K  79% non-CC  47% F4  54% Null Jacobson I, et al. AASLD 2013. Abstract LB-3.

53. Summary Viral Hepatitis shares many transmission routes with HIV Treatment options are available for both B & C however only C can be cured Side effects of current treatments require good nursing management New therapies are coming but are expensive

55. Case Study

56. HEPATITIS C / HIV CO-INFECTION Case Study James Hand HIV/HCV Clinical Research Manager

57. 34yr MSM HIV+ past 3 years (routine screening) Initial CD4 = 570 Present CD4 = 400 HIV viral load = 92,000 Not had any antiretrovirals to date Partner (also HIV+) for past 3 years turns out to be HCV+ ‘Plenty of unprotected sex…’

58. Question…….? “How would it be best to check if he has become infected with hep C?” 1.Hepatitis C antibody 2. Abnormal LFTs 3. Hepatitis C PCR (i.e. viral load) 4. Hepatitis C Antibody & Viral Load

59. FINDINGS……. HCV confirmed….. Hep C Ab+ Genotype 1a HCV viral load 1,250,000 ALT 52 Other LFT and clotting normal Examination Unremarkable

60. Assessing the patient: What factors are relevant? Various factors may make his liver even worse: Alcohol Other drugs/recreational drugs Other liver disease e.g. HBV Degree of liver fibrosis Weight & insulin resistance Black African race

61. Question? When trying to assess his degree of liver fibrosis which of the following techniques are as good in co-infection as mono-infection? 1. Commercial blood assays – e.g. Fibrotest 2. Fibroscan 3. Liver Biopsy 4. Ultrasound

62. Liver Fibrosis Staging

63. Patient asks….. Is this really bad news? Will my HIV make it worse?

64. Patient asks…. ‘Can you cure me?’

65. What should we treat first – HIV or Hep C? Liver Biopsy Score = 2/6 Probably some fibrosis CD4 = 400 HIV VL = 92,000 (WT) Not had ARVs

66. A balance of what to treat first REASONS TO TREAT HCV FIRST Can we wait? Drug-drug interactions If get a rash/adverse event what is the cause? Increased hepatotoxicity with ARVs if HCV+ REASONS TO TREAT HIV FIRST Can we wait? Response to HCV Rx better at higher CD4 Response to HCV Rx better when HIV controlled CD4 will drop with PEG-IFN