1. Managing patients with HIV, TB or Hepatitis C – What do I need to know? Hepatitis C management Dr Soek-Siam Tan Saturday 13 August 2011 Recovery-Oriented ADdiction Medicine – Asia-Pacific Seminars (ROADMAPS) – Bali Meeting 2011 “Safety, Quality, Efficacy”

2. Content and Learning Objectives  Explain the burden and natural history of HCV infection.  Summary and interpretations of diagnostic tests : laboratory tests, liver biopsies and noninvasive tests.  Overview of Hepatitis C treatment: the goals, efficacy and guidelines (opioid-dependent and HIV/HCV co- infected patients).  Overview of the newly approved Hepatitis C treatment - the Direct Acting Anti-virals (DAAs).  Suggestions for day to day clinical practice.

3. The burden and natural history of HCV infection

4. Burden of HCV in Drug Users CountryPrevalence of HCV China (pooled data on IDU) 61.4% Indonesia (639 prisoners for drug-related offences) 18.6% (correspondence from delegates: 60–80%) Taiwan (577 male heroin abusers) 74.9% Malaysia (552 not-in-treatment drug users ) 65.4% Xia X et al. Public Health. 2008;122(10):990-1003 Nelwan EJ et al. Trop Med Int Health. 2010 Dec;15(12):1491-8 Liao KF et al. South Med J 2006 Apr;99(4):348-51. Vicknasingam B et al. Drug Alcohol Rev. 2009 Jul;28(4):447-54. Sievert W et al. Liver Int 2011 31 Suppl 2: 61-80 The prevalence of HCV in general population in the region is 1–2% (4.4% in Taiwan).

5. Time After Exposure Symptoms 0 400 600 800 1000 ALT (IU/L) 02 46810122412345 6 Anti-HCV positive (6-8 weeks) Weeks Months HCV RNA positive (10-14 days) 200 7 Normal ALT Course of Acute HCV Infection Asymptomatic in 50–90% of cases Symptoms are mild and non specific Jaundice is uncommon Only occasionally result in acute liver failure

6. The Natural History of HCV Infection Stable 60% to 90% HCC or Decompensation 1% to 3%/yr Death from complications of cirrhosis= 4%/yr, from HCC = 33% 1 st yr. Stable 97% to 99%/yr Resolved 10% to 50% Acute HCV Cirrhosis 10% to 40% Chronic HCV 50% to 90% Progressions take decades But accelerated by alcohol use, in diabetics, older age at infection, viral co- infection Santantonio T et al. J Hepatol 2008;49:625–633. Wiegand J et al. J Antimicrob Chemother 2008;62:860–865. Afdhal NH. Semin Liver Dis 2004;24; 3–8. Thompson CJ, et al. Health Technol Assess 2007;11:1–206. Yang JD, et al. Nat Rev Gastroenterol Hepatol 2010;7:448–458. Bartosch B et al. J Hepatol 2009;51:810–820.

7. Summary and interpretations of diagnostic tests

8. Anti-HCV antibody and HCV RNA Anti-HCV Measures antibody Sensitivity: 97% to 100% False negatives may occur Chronically immunosuppressed Transplantation recipients Chronic renal failure on dialysis HIV positive False-positive reactions may occur Positive predictive value 95% with risk factors and elevated ALT 50% without risk factors and normal ALT Is a screening test HCV RNA Measures the virus RNA. A sensitive assay (real-time PCR) has lower limit of detection of 50 IU/ml or less. False negatives may occur Presence of inhibitors (e.g. heparin) Very low levels Problems in methods of collection, processing and storage The use of HCV RNA tests Diagnosis of active HCV infection To monitor treatment-use viral kinetics for response guided therapy To assess response to treatment.

9. Interpretations of HCV assay Anti-HCVHCV RNAInterpretations Positive Acute or chronic HCV infection (to differentiate: need history and clinical context) PositiveNegativeResolution of HCV or Acute HCV already with low viraemia NegativePositiveEarly acute HCV HCV in immunosuppressed False-positive HCV RNA Negative Absence of HCV infection GHANY et al. HEPATOLOGY, Vol. 49, No. 4, 2009

10. Normal ALT is an Imperfect Marker of Liver Disease Severity  There are significantly less liver fibrosis observed in patients with persistently normal ALT, however fibrosis and cirrhosis are found in patients with normal ALT.  Therefore, ALT should not be used alone to decide on liver disease severity or Rx. 0 20 40 60 80 100 No fibrosisMildBridgingPortal Severity of Liver Disease Patients (%) Normal ALT (n = 58) Elevated ALT (n = 37) 23 19 39 19 26 24 6 16 Cirrhosis 6 22 Martinot-Peignoux M, et al. Hepatology. 2001;34:1000-1005. Nutt AK, et al. Am J Med. 2000;109:62-64. Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

11. HCV Genotypes-the clinical significance Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355. McHutchison JG, et al. N Engl J Med 2010; 362:1292  There is 30% genetic diversity in HCV genotypes 1 to 6 Multiple subtypes: a, b, c, etc  Genotype is a pretreatment predictor of response Genotype 1: least responsive to therapy  Determines dose and duration of therapy Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000–1200 mg Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg  All patients should have genotype tested before initiating treatment.  Subtype 1a has a much lower genetic barrier than subtype 1b to drug resistances in the new DAAs

12. HCV Genotype Predicts Response to treatment (SVR)  PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800 mg/day for 48 wks  PegIFN alfa-2a 180 µg/wk + weight-based RBV (1000 or 1200 mg/d) for 48 wks Manns M, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982. 46 76 56 Overall Genotype 1 Genotype 2/3 298140n=453 42 82 100 80 60 40 20 0 54 OverallGenotype 1 Genotype 2/3 SVR (%) 348163n=511 100 80 60 40 20 0

13. Virologic Definitions of Treatment Response at different time points Types of response Definitions RVRHCV RNA negative (< 50 IU/mL) at Wk 4 of therapy EVR Complete EVR HCV RNA positive at Wk 4 but negative at Wk 12 Partial EVR HCV RNA positive at Wks 4 and 12 but ≥2 log 10 IU/mL drop from baseline at Wk 12 Non-EVR< 2 log 10 IU/mL drop from baseline at Wk 12 ETRHCV RNA negative (<50 IU/mL) at ETR SVR HCV RNA negative (<50 IU/mL) at 24 weeks after stopping treatment RVR = Rapid Virological Response, EVR= Early Virological Response ETR = End of Treatment Response, SVR = Sustained Virological Response

14. Assessment of liver disease severity  Is recommended prior to therapy unless already have clinical evidence of cirrhosis.  Liver biopsy is the reference method. The risk of severe complications is very low (1/4000–10,000) but includes death.  From the liver tissue, we assess for Histological features consistent with chronic hepatitis C. Liver disease severity: Necroinflammation (grading) and Fibrosis (staging). {Scoring systems: METAVIR, Scheuer, Ishak, and Knodell’s HAI. Metavir score: F0 =no fibrosis, F1 =portal fibrosis without septa, F2 =portal fibrosis with few septa, F3 =numerous septa without cirrhosis, F4 =cirrhosis. A0 =no activity, A1 =mild, A2 =moderate, A3 =severe} Concomitant liver disease ( e.g. CHC with drug-induced liver injury). Cirrhosis - cirrhotics have altered response to treatment and prognosis. In addition they need surveillance for liver cancer and varices.

15. Non-invasive methods are available for assessment of inflammation and fibrosis A liver biopsy is able to examine 1/50,000 of the liver. Depending on where the biospy needle is there is potential for sampling errors Transient elastrography (elastic wave, measure multiple points and larger liver volume) APRI, AST/ALT ratio, Forns Index: use ALT, AST, PT, platelets Specific indirect markers of liver fibrosis Direct markers of liver fibrosis Combinations of direct and indirect markers Bedossa P, et al. Hepatology. 2003;38:1449-1457

16. Ge D, et al. Nature. 2009;461:399-401. Recent predictor of SVR: IL28-B Genotype One of the recent breakthroughs in hepatitis C treatment has been the finding that genetic polymorphism of rs12979860 can influence outcome. » near IL28-B which determines activity of IFN lambda-3 » T (unfavorable) and C (favorable) alleles Overall TT TC CC African AmericanEuropeanHispanic TT TC CC

17. Thomas D, et al. Nature. 2009;461:798-801. C allele frequency C allele frequency = T allele frequency T allele frequency = IL28B Genotype Distribution IL28B Genotype Distribution Favourable, clinical use to be defined

18. IL28B associations in CHC  IL28B polymorphisms associated with – Higher SVR rates. – Higher RVR rates. – Higher HCV RNA. – Higher LDL levels. – Higher baseline ALT levels. – Higher rate of spontaneous viral clearance. – In liver transplant setting - higher SVR, donor with protective genotype improves outcome in recipient with unfavourable genotype. Ge D, et al. Nature. 2009;461:399-401. Mangia A, et al. AASLD 2010. Abstract 897. Liu L, et al. AASLD 2010. Abstract 231. Li JH, et al. Hepatology 2010; 51:1904-1911. Thompson AJ, et al. AASLD 2010. Abstract 1893. Thomas DL, et al. Nature. 2009;461:798-801. Fukuhara T et al. Gastroenterology 2010; 139:1577-1585 Charlton MR et al. hepatology 2011;53:317-324. Eurich D et al J Hepatol 2010;52:S40

19. VIRAL FACTORS HCV Genotype Viraemia level HIV infection HOST FACTORS IL28b Genotype African Race Older age Obesity Baseline predictors of cure with current treatment Peg-IFN plus Ribavirin DISEASE FACTORS Cirrhosis

20. Overview of Hepatitis C treatment

21. The goals of Hepatitis C Treatment Primary Eradicate the virus Secondary Prevent progression to cirrhosis Reduce incidence of hepatocellular carcinoma Reduce need for transplantation Enhance survival Davis GL, et al. J Hepatol. 1995;22(suppl 1):110-114. Lindsay KL. Hepatology. 1997;26(suppl 1):71S-77S.

22. 21,836 patients received PEG/RBV in VA hospitals » 16,864 completed treatment Backus L, et al. Hepatology 2010; 52: 428A Chronic Hepatitis C Antiviral Efficacy in the ‘Real World’

23. Many large trials excluded IDUs unless they had substantial period of abstinence. SVR among IDUs = 15.8–94.1% (median =40.6%) for CHC, 50 - 100% (median =69.2%) for AHCV. Compliance data: non-compliance rates for IDUs vs non IDUs are 6.8% (median =12.7%) vs 4.9% (median =7.3%). In a series (n=109) with 75% ever reporting IDU. The 80/80 PEG- IFN adherence rate was 82%. IDU prior to or during treatment did not impact adherence. Risk of re-infection: 3.2 per 100 p-y overall and 5.3 per 100 p-y among those reporting injecting following SVR. Grebely J et al. J Hepatol. 2011 ;55(1):76-85. Hellard M et al CID 2009:49; 561-573. Grebely J et al. J Gastroenterol Hepatol. 2010;25(7):1281-4. IDUs with chronic hepatitis C - are they different?

24. HCV treatment guidelines- sections on treating IDU  AASLD 2009: “Treatment of HCV infection can be considered for persons even if they currently use illicit drugs or who are on a methadone maintenance program, provided they wish to take HCV treatment and are able and willing to maintain close monitoring and practice contraception (Class IIa, Level C). Persons who use illicit drugs should receive continued support from drug abuse and psychiatric counseling services as an important adjunct to treatment of HCV infection (Class IIa, Level C)”.  EASL 2011: “Treatment of patients with active illicit drug abuse has to be decided on an individual basis and should be carried out in an interdisciplinary team together with addictologists (C2). Treatment of patients with active illicit drug abuse on stable maintenance substitution treatment can be safely performed in an interdisciplinary team involving addictologists and yields only slightly reduced SVR-rates compared to conventional HCV-patients (B2).” Journal of Gastroenterology and Hepatology 22 (2007) 615–633. Ghany et al. HEPATOLOGY, April 2009. EASL CPG on management of Hepatitis C virus infection. Journal of Hepatol 2011(55) 245–264

25. HCV/HIV co-infection is common  Progression of liver disease is accelerated in patients with HIV- HCV co-infection, esp those with a low CD4-positive cell count and impaired immune function.  Therefore early antiretroviral therapy should be considered in patients with HIV-HCV co-infection.  Rates of SVR are lower than in monoinfected patients.  Indications for treatment are the same as the monoinfected but more urgent in view of accelerated liver disease and also successful treatment of HCV reduces the hepatoxicity of HAART.  Before starting anti-HCV treatment, CD4-positive cell count should be >200 cells/ul. Bart G et al. Addiction 2008 Apr;103(4):681-6. Qurishi N et al. Lancet 2003;362:1708–1713.

26. HCV treatment guidelines - sections on HCV/HIV co-infection AASLD 2009 guidelines: Hepatitis C should be treated in the HIV/HCV co-infected patient in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy. Initial treatment of hepatitis C in most HIV infected patients should be peginterferon alfa plus ribavirin for 48 weeks at doses recommended for HCV mono-infected patients. EASL 2011 guidelines:  HIV/HCV patients need 48 weeks of therapy, and treatment should be extended to 72 weeks in patients who are still HCV RNA-positive at week 12 (DVR), whatever the HCV genotype.  Patients infected with genotypes 2 or 3 with low baseline HCV RNA level (<400,000 IU/ml) and mild fibrosis who achieve an RVR may only need 24 weeks of therapy. Ghany et al. HEPATOLOGY, April 2009. EASL CPG on management of Hepatitis C virus infection. Journal of Hepatol 2011(55) 245–264

27. Newly approved treatment for hepatitis C

28. Approved therapies for CHC Interferon alfa (conventional/PEG) Inhibits viral entry into cells Inhibits viral replication Enhances cytolytic (killer) T-cell activity Stimulates killer cell activity Ribavirin Mechanism of action not well understood Combination with IFN enhances sustained virologic response rates by decreasing relapse Teratogenic As of May 2011 US FDA has approved 2 new medications: Telaprevir and Boceprevir Are protease inhibitors (HCV NS3/4A, HCV NS3) To be used together with PEGIFN and Ribavirin. Improves sustained virological response in treatment naïve and previous failed Genotype 1 CHC

29. Dosing: Peg-IFN = Peg-IFN alfa-2a 180 µg/week, RBV = RBV 1,000 or 1,200 mg/day,TVR = TVR 750 mg q8h 2404872 Weeks 126036 Peg-IFN + RBV Follow-up TVR + Peg-IFN + RBV T12/PR24 (n=350) Follow-up SOC48 (control) (n=350) Peg-IFN + RBV Follow-up T12/PR12 (n=350) TVR + Peg-IFN+RBV Telepravir plus SOC in Rx-naïve GT1 HCV Jacobson I, et al. N Engl J Med 2011; 364: 2405-16 ADVANCE Phase III Registration Study

30. Telepravir plus SOC in Rx-naïve GT1 HCV Jacobson I, et al. N Engl J Med 2011; 364: 2405-16 ADVANCE Phase III Registration Study Primary Efficacy Endpoint: SVR24

31. Dosing: Peg-IFN = Peg-IFN alfa-2a 180 µg/week, RBV = RBV 1,000 or 1,200 mg/day,TVR = TVR 750 mg q8h 2404872 Weeks 126036 Follow-up Peg-IFN + RBV TVR + Peg-IFN + RBV T12/PR48 (n=268) Follow-up SOC48 (control) (n=133) Peg-IFN + RBV Telepravir plus SOC in Previous Non-responder GT1 HCV REALIZE Phase III Registration Study Zeuzem S, et al. N Engl J Med 2011; 364: 2417-28 Follow-up Lead-in 4/ T12/PR48 (n=264) PegIFN + RBV Peg-IFN + RBV TVR + Peg-IFN + RBV

32. REALIZE Phase III Registration Study Zeuzem S, et al. N Engl J Med 2011; 364: 2417-28 Telepravir plus SOC in Previous non-responder GT1 HCV

33. Relapsers Zeuzem S, et al. N Engl J Med 2011; 364: 2417-28 Telepravir plus SOC in GT1 according to types of previous non response Partial Non Responders Null Responders

34. Weeks12242848728 TW 8-24 Undetectable Follow-up 44 wks Follow-up 24 wks TW 8-24 Detectable Placebo + P/R 20 wks Decision point for long vs. short therapy BOC + P/R 24 wks P/R 4 wks Arm 2 BOC RGT (n=368) Follow-up 24 wks BOC + P/R 44 wks P/R 4 wks Arm 3 BOC/ PR48 (n=362) Stopping Rule Follow-up 24 wks Placebo + P/R 44 wks P/R 4 wks Follow-up 24 wks Arm 1 PR48 Control (n=363) Lead-in Stopping Rule: Patients with detectable HCV-RNA at week 24 were discontinued from treatment for futility. Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R) using weight based dosing of 600-1400 mg/day in a divided daily dose. BOC administered 800 mg TID. SPRINT 2: Boceprevir plus SOC in Treatment- naïve HCV GT1

35. Boceprevir plus SOC in Rx-naïve GT1 Efficacy: Sustained Virologic Response Poordad F, et al. Hepatology 2010; 52 (S1) [abstract LB-4] Non-Black Patients p<0.0001 Black Patients p=0.044 p =0.004

36. Lindenbach BD, Rice CM. Nature. 2005;436(suppl):933-938. Direct Acting Antivirals (DAAs) Virion assembly RNA replication Transport and release Receptor binding and endocytosis Fusion and uncoating Translation and polyprotein processing (+) RNA 4 Polymerase InhibitorsX 1 Anti-E mAb Fusion oligosX 5 Cyclophyllin InhibitorsX 2 Ribozyme Antisense siRNAsX Protease Inhibitors X 3  -Glucosidase InhibitorsX 6

37. TargetAgentPhase NS5b Non- nucleoside analogue (NNA) Filibuvir Phase II Tegobuvir JTK-003 BI207127 BMS-824393 VX-222 ABT-072 ABT-333 MK3281 ANA598 HCV-796 Phase I IDX375 VX759 Phase II PF4878691 Phase I RO5471354 GS-9669 TargetAgentPhase NS5a Non- nucleoside analogue A-831 Phase I AZD7295 Phase II BMS790052 GS-5885 PPI-461 PPI-668Preclin PPI-1833Preclin BMS-824393Preclin PPI-437Preclin TargetAgentPhase NS5b Nucleoside Analogue (NA) RG7128Phase III R1626Phase II NM283Phase II PSI-7977Phase II PSI-938Phase I ALS-002158Phase I ALS-002200Phase I GS-6620Phase I IDX184Phase I RG7348Phase I MK-0608Phase I TargetAgentPhase Cyclophyllin B inhibitors DEBIO-025 Phase II NIM811 Phase I More Direct Acting Antivirals

38. Suggestions for day to day clinical practice

39. Recommendations for screening  Test for HCV (anti-HCV) AASLD 2009 recommended HCV screening: Persons who have injected illicit drugs in the recent and remote past including those who injected only once and do not consider themselves to be drug users. Normal ALT does not mean no significant liver disease or no viral hepatitis. For anti-HCV antibody first then HCV RNA HBV (HBsAg, anti-HBs), and HAV (anti-HAV IgG)  If HCV RNA is detected Determine if patient wants treatment and could treatment for HCV infection be successful. Offer counseling and secondary prevention interventions to those not interested in treatment. Review treatment options regularly.

40. Assessment prior to treatment  Clinical - comprehensive history taking and clinical assessments. (NB Any cautions or contraindications to treatment. Motivations for treatment.)  Laboratory - FBC, LFT, RP, ANA, TFT, Anti-HAV total and HBsAg/antiHBs (if negative need HAV/HBV vaccination) HCV RNA and genotype. Liver Biopsy/Fibroscan. Others if clinically indicated  Education – avoid transmission, vaccination, natural history of HCV, treatment: efficacy, durations, AEs, follow-up while on treatment. Address modifiable co-factors – body weight, alcohol consumption

41. Clinical and Laboratory Monitoring during treatment  Patients should be monitored during therapy to assess the response to treatment and for the occurrence of adverse effects e.g. depression and etc.  Monthly visits during treatment until the end of therapy. FBC, serum creatinine, LFT. Thyroid function: every 12 wks while on treatment HCV RNA. -Assess and monitor viral kinetics during treatment Wk4 (RVR), Wk 12 (EVR), Wk 24. -ETR (at the end of treatment). -SVR (6 mo after stopping).

42. Adverse Event, % Peginterferon alfa-2a/b + Ribavirin Injection-site reaction23-75 Fatigue/asthenia65-66 Pyrexia (fever)41-46 Rigors25-48 Pain10 Nausea/vomiting14-43 Abdominal pain8-13 Diarrhea11-22 Leukopenia6-14 Anemia11-12 Neutropenia26-27 Anorexia24-32 Weight decrease10-29 Right upper quadrant pain 12 Myalgia40-56 Most Common Adverse Events During HCV Therapy (≥ 10% of Patients) PEG-Intron [package insert]. Kenilworth, NJ: Schering Corp; July 2006. Pegasys [package insert]. Nutley, NJ: Roche Pharmaceuticals; May 2005. Adverse Event, % Peginterferon alfa-2a/b + Ribavirin Arthralgia22-34 Musculoskeletal pain21 Headache43-62 Dizziness14-21 Resistance mechanism disorders 12-18 Irritability/anxiety/nervousness33-47 Insomnia30-40 Depression20-31 Concentration impaired10-17 Dyspnea13-26 Cough10-23 Pharyngitis12 Alopecia28-36 Pruritus19-29 Dermatitis/rash16-24 Dry skin10-24

43. Managing Hepatitis C Treatment-Associated Adverse Events.  Know your patient  a supportive family member; establish mutual respect and patient’s role in the care process.  Address risk factors for adverse effects (smoking, obesity, previous mental health issues); obtain detailed history of substance use.  Inform and prepare your patient for treatment-related adverse events (wait if have upcoming personal events that maybe stressful, start some form of exercise).  Monitor your patient and manage adverse effects.  Guide your patient to success with adherence strategies and a multidisciplinary team approach.

44. THANK YOU

45. CASE - RW

46. 43 year-old male. Previous IDU and other recreational drug use (stopped for 4–5 years). HIV diagnosed in 1994 on HAART therapy {Stavudine+Lamivudine+Nevirapine (hepatotoxicity) ->Stavudine (lipodystrophy) +Lamivudine +Stocrin -> Lamivudine +Zidovudine +Efavirenz} CD4=588 Pulmonary TB complicated with abscess formation and had anti-tuberculous therapy for 9–12 months durations in 1994, 2001 and 2005. Chronic hepatitis C

47. First Co-infection Clinic Visit History: - Occasional lethargy -Denied any symptoms to suggest liver decompensation. - There was no history of depression or suicidal attempts -Single, works as a security guard for 2 years. Smokes 10/day. No ethanol. - Buprenorphine-naloxone for the last 4 years (4 mg day and 2 mg night) Clinical assessment:  BP=130/80  Facial wasting from lipodystrophy  No cutaneous stigmata of chronic liver diseases Plan: o Blood investigations : LFT, FBC, RP, FBS, ANA, TFT, HBsAg, anti-HBs, anti- HAV (total), HCV RNA, HCV genotype, US o Viral Hepatitis Education o Discussed natural history, available treatment, duration, SE, outcomes, treatment care plan.

48. Second clinic visit Patient was well and very keen for treatment. Since the last visit, he had looked up the internet for more information. He said his close friend who was treated for CHC is supportive and visiting him regularly. Reviewed results: Total protein=78 g/l, Albumin=48 g/l, Total bilirubin=17umol/l, Alkaline phosphatase= 60 u/l, Alanine transaminase=42 u/l FBC, RP, TFT, FBS all normal ANA not detected HBsAg, anti-HBs and anti-HAV (total) were negative->recommended HBV and HAV vaccination HCV RNA= 320,000 IU/ml Genotype 3a

49. How would you manage the patient at this time? A. Initiate treatment with peginterferon plus ribavirin after discussion with the addiction specialist who looked after him and obtaining a liver biopsy. B. Treatment is not indicated because the ALT of 42 g/l is only mildly elevated. C. Treatment is contra-indicated given his past history of injection drug use, TB and co-infection with HIV.

50. How would you manage the patient at this time? A. Initiate treatment with peginterferon plus ribavirin after discussion with the addiction specialist who looked after him and obtaining a liver biopsy. B. Treatment is not indicated because the ALT of 42 g/l is only mildly elevated. C. Treatment is contra-indicated given his past history of injection drug use, TB and co-infection with HIV.

51. A. Admission for liver biopsy: Uncomplicated percutaneous liver biopsy. Fibroscan (Transient elastography) = 4.4 kPa, IQR=0.5, Success Rate=100%. EASL 2011: “Transient elastography (TE) can be used to assess liver fibrosis in patients with CHC provided that consideration is given to factors that may adversely affect its performance such as obesity, age and biochemical necroinflammatory activity” “The combination of blood tests or the combination of TE and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty”

52. Specimen labeled as liver biopsy consists of a strips of yellowish tissue measuring 1.9cm in length, entirely submitted in one block. SP Final Histology Section shows a strip of liver tissue and 4 to 6 portal tracts present. MODIFIED HAI GRADING A. Periportal or periseptal (interface) Hepatitis Score Absent 0 B. Confluent Necrosis Score Absent 0 C. Focal (spotty) lytic necrosis, Apoptosis, and Score Focal Inflammation (at x10 objective) One focus or less 1 D. Portal Inflammation Score Mild, some or all portal areas 1 Degree of fibrosis Score No fibrosis 0 SP Final Diagnosis Liver biopsy : Consistent with Hepatitis C, inflammatory score : 2 fibrosis score : 0 ADDITIONAL FEATURES: Bile - duct inflammation and damage -nil Lymphoid follicles -nil Steatosis : mild, mixed ( macrosteatosis 10% to 15% of hepatocytes ). Hepatocellular dysplasia, large - or small - cell -nil Adenomatous hyperplasia -nil Iron or copper overload -nil Intracellular inclusion (eg. PAS - positive globules, Mallory bodies) –nil Orcein stain negative. HCV esp G3 Stavudine Corresponds to TE 4.4 kPa

54. Patient was keen and very motivated to start therapy. His HAART were changed from Lamivudine+Zidovudine +Efavirenz back to Stavudine+Lamivudine+Stocrin to minimize the risk of anemia (dropped AZT). Started on Pegylated interferon alfa 2a 180 mcg sc once weekly and oral Ribavirin 800 mg/ day on 26.7.08. Received education by our pharmacist on the preparation for injection and the techniques, storage of medication in the fridge, disposal of needles, how to maintain cold chain etc. Education by our nurse on how to manage and recognize common side-effects (use of paracetamol 30 mins before injection, increase fluid intake), contact person.

55. HIV and HCV/HBV co-infection As mortality from AIDS has fallen, there is increasing recognition of the importance of end stage liver disease as a cause of significant morbidity and mortality in patients coinfected with HCV and HBV. Evidence showed that co-infection increased likelihood of ESLD with a faster progression to ESLD. All antiretrovirals have the potential to cause acute and long-term hepatotoxicity and this risk is increased by 2-3 x in the presence of CHB/CHC. This increased risk of hepatotoxicity disappears if the chronic viral hepatitis is successfully treated. Rosenthal E et al. AIDS 2003; 17: 1803–1809. Labarga P et al. J Infect Dis 2007;196: 670–676.

56. In your expert opinion, do you think he will be able to adhere to the 48 weeks treatment with 4 weekly visits?  Yes  No

57. Wk 2: Fever easily managed with paracetamol. Wk 4: HCV RNA detected=non RVR. Wk 6: Weight loss from 55kg to 52 kg. Wk10: Shortness of breath-occasional rhonchi. Advised to stop smoking. Wk 14: Further decrease in body weight to 51 kg. Discussed HAART regime with the ID specialist Changed Stavudine to Tenofovir. Wk18: Hair loss – reassurance/mild shampoo etc. Wk 22 to Wk 48: No new complaints. – Body weight stable at 50–52kg. – Bup-nx dose remained the same – throughout the 48 weeks treatment

58. HCV RNA was negative at the end of treatment in June 2009 (ie achieved ETR). HCV RNA remained negative at 24 weeks post treatment. Therefore he achieved SVR

60. CD4 counts PEG and RBV

61. THANK YOU