MANAGEMENT OF HEPATITIS B AND HEPATITIS C.pptx

Management of hepatitis B and hepatitis C

1. MANAGEMENT OF HEPATITIS B AND HEPATITIS C BY: DR. AMMAR SABIR SIDDIQUI JR-III DEPARTMENT OF MEDICINE, KGMU

2. HBsAg Anti-HBs Anti- HBc HBeAg Anti- HBe Interpretation + − IgM + − Acute hepatitis B, high infectivity + − IgG + − Chronic hepatitis B, high infectivity + − IgG − + Late acute or chronic hepatitis B, low infectivity − + IgG − +/− Recovery from hepatitis B − + − − − Immunization with HBsAg (after vaccination)

3. Initial assessment of subjects with HBV infection HBV markers Liver disease Marker HBsAg Biochemical parameters: ALT HBeAg Fibrosis markers: non-invasive markers of fibrosis ( elastography ) or liver biopsy HBV DNA

4. Indications for treatment This is based mainly on the combination of three criteria: Serum HBV DNA levels Serum ALT levels Severity of liver disease (decided by liver histology/non invasive fibrosis markers)

5. HBsAg-positive Ref.- AASLD 2018 Hepatitis B Guidelines

6. HBsAg-positive Ref.- AASLD 2018 Hepatitis B Guidelines

7. Fibrosis staging (F) and inflammatory activity (A) were decided according to the METAVIR system. Fibrosis staging was divided into F0-F4 F0 = no fibrosis F1 = portal fibrosis without septa F2 = periportal fibrosis with few septa F3 = septal fibrosis with many septa F4 = cirrhosis Inflammatory activity was divided into A0-A3 A0 = no histologic necro-inflammatory activity A1 = minimal activity A2 = moderate activity A3 = severe activity

8. TREATMENT GOAL The main goal of therapy in Acute hepatitis B to prevent the risk of acute or sub acute liver failure Chronic HBV infection to improve survival and quality of life by preventing disease progression, and consequently HCC development The induction of long-term suppression of HBV replication represents the main end point of current treatment strategies, while HBsAg loss is an optimal endpoint(rarely achieved)

9. Acute hepatitis B More than 95% of adults with acute HBV hepatitis do not require specific treatment, because they will fully recover spontaneously Only patients with severe acute hepatitis B , characterised by coagulopathy (INR>1.5) or protracted course (persistent symptoms or marked jaundice for >4 weeks) or signs of acute liver failure, should be treated with NA and considered for liver transplantation Nucleos (t)ide analog therapy in this situation is generally safe, and preferred agents include TDF, TAF, entecavir, or lamivudine, but Peg IFN is contraindicated in patients with abnormal liver function. The optimal duration of therapy is unknown, and the endpoint of therapy is confirmed by HBsAg loss or seroconversion .

10. APROVED DRUGS CLASSIFICATION PegIFN Nucleoside analogues Nucleotide analogues PegIFN α - 2a Lamivudine (LAM) Adefovir dipivoxil (ADV) PegIFN α - 2b Telbivudine (TBV) Tenofovir disoproxil fumarate (TDF) Entecavir (ETV) Tenofovir alafenamide (TAF)

11. Low barrier to HBV resistance High barrier to HBV resistance Lamivudine (LAM) Entecavir (ETV) Adefovir dipivoxil (ADV) Tenofovir disoproxil fumarate (TDF) Telbivudine (TBV) Tenofovir alafenamide (TAF)

12. Drug Dose in Adults Pregnancy Category Side Effects Peg-IFN 180 µg weekly C Flu-like symptoms , fatigue, mood disturbances, myelosuppression , autoimmune disorders in adult , hepatitis flares , decompensation of liver disease Lamivudine 100 mg daily C Pancreatitis ,Lactic acidosis Telbivudine 600 mg daily B Creatine kinase elevations and myopathy , Peripheral neuropathy , Lactic acidosis Entecavir 0.5 or 1.0 mg daily C Lactic acidosis Adefovir 10 mg daily C Acute renal failure , Fanconi syndrome , Nephrogenic diabetes insipidus , Lactic acidosis Tenofovir 300 mg daily B Nephropathy , Osteomalacia , Fanconi syndrome , Lactic acidosis

13. Features PegIFNa NA(ETV, TDF, TAF ) Route of administration Subcutaneous injections Oral Treatment duration 48 weeks Long-term Tolerability Low High Contraindications Many (i.e., decompensated disease) None (dose adjustment according to eGFR ) Dose adjustments in patients with eGFR <50 ml/min are required for all NA, except for TAF ( CrCl <15 ml/min)

14. Features PegIFNa ETV, TDF, TAF Level of viral suppression Moderate Universally high Effect on HBeAg loss Moderate Low in the first year, increases to moderate during long-term treatment Effect on HBsAg levels Variable Low: slowly increases with treatment time Risk of relapse after treatment cessation Low Moderate

15. Indications for selecting TAF over TDF Age >60 years Bone disease Chronic steroid use or use of other medications that worsen bone density History of pathological fracture Osteoporosis Renal function alteration eGFR<60 ml/min/1.73 m2 Albuminuria>30 mg/24 h or moderate dipstick proteinuria Low phosphate (<2.5 mg/dl) Hemodialysis

16. Definitions of response Virological response For NA therapy is defined as undetectable HBV DNA by a sensitive polymerase chain reaction (PCR) assay with a limit of detection of 10 IU/ml. Sustained off-therapy virological response could be defined as serum HBV DNA levels <2,000 IU/ml for at least 12 months after the end of therapy. For PegIFNa therapy Virological response is defined as serum HBV DNA levels <2,000 IU/ml. It is usually evaluated at 6 months and at the end of therapy. Sustained off-therapy virological response is defined as serum HBV DNA levels <2,000 IU/ml for at least 12 months after the end of therapy

17. Serological response For HBeAg are HBeAg loss and HBeAg seroconversion , i.e., HBeAg loss and development of anti- HBe (only for HBeAg -positive patients). For HBsAg are HBsAg loss and HBsAg seroconversion , i.e., HBsAg loss and development of anti-HBs (for all patients). Biochemical response Defined as a normalisation of ALT levels based on the traditional ULN (40 IU/L). Histological response Defined as a decrease in necroinflammatory activity without worsening in fibrosis compared to pretreatment histological findings.

18. NA discontinuation NAs should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion In non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who completed at least 12 months of therapy, treatment guidelines recommend continuing treatment for at least 12 months after HBeAg seroconversion Discontinuation of NAs in selected non-cirrhotic HBeAg -negative patients who have achieved long-term (≥3 years) virological suppression under NA(s) may be considered (close monitoring can be guaranteed)

19. Since NA therapy does not usually achieve HBV eradication and rarely results even in HBsAg loss, long-term therapeutic regimens are given in the majority of NA treated CHB patients. NA therapy is continued lifelong in individuals with established cirrhosis

20. Treatment failure Primary non-response : defined by a less than one log10 decrease of serum HBV DNA after 3 months of therapy. Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 12 months of therapy in compliant patients. Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than1log10 IU/ml compared to the nadir (lowest value)HBV DNA level on-therapy, it may precede a biochemical breakthrough, characterised by an increase in ALT levels.

21. HIV co-infected patients All HIV-positive patients with HBV co-infection should start antiretroviral therapy(ART) irrespective of CD4 cell coun t due to the increased risk of fibrosis progression, cirrhosis and HCC Recommended regimens include a tenofovir-based regimen (TDF or TAF) in combination with either lamivudine or emtricitabine to avoid the development of HIV resistance to tenofovir.

22. HDV co-infected patients At present, PegIFNa is the only available drug that has been proven to have some antiviral efficacy against chronic HDV infection PegIFNa for at least 48 weeks is the current treatment of choice in HDV-HBV co-infected patients with compensated liver In HDV-HBV co-infected patients with ongoing HBV DNA replication (HBV DNA levels being persistently above 2,000 IU/ml), NA therapy should be considered

23. HCV co-infected patients Treatment of HCV with direct-acting antivirals (DAAs) may cause reactivation of HBV. Patients fulfilling the standard criteria for HBV treatment should receive NA treatment HBsAg -positive patients undergoing DAA therapy should be considered for concomitant NA prophylaxis until 12 week post DAA , and monitored closely HBsAg-negative, anti-HBc positive patients undergoing DAA should be monitored and tested for HBV reactivation with serum HBV DNA levels measured at least once during DAA therapy, with initiation of HBV treatment when the serum HBV DNA level increases by 1 log IU/mL

24. Pregnancy Screening for HBsAg in the first trimester of pregnancy is strongly recommended The highest risk period for HBV transmission is thought to occur intrapartum, although intrauterine transmission may also occur. For women who become pregnant on nucleos (t)ide analog therapy, treatment is continued throughout the pregnancy provided the patient is receiving TDF, telbivudine, or lamivudine Although breastfeeding while on nucleos (t)ide analog therapy is officially contraindicated because small amounts of drug can be detected in breast milk, adverse events have not been observed thus far.

25. In all pregnant women with high HBV DNA levels (>200,000 IU/ml) or HBsAg levels >4 log10 IU/ml, antiviral prophylaxis with TDF should start at week 28–32 of gestation and continue for upto 12 weeks after delivery The prevention of HBV perinatal transmission , which is considered to occur mainly at delivery, and causes the majority of chronic HBV infection is based on the combination of HBIG and vaccination given within 12h of birth . This prophylaxis reduces the rate of perinatal transmission from >90% to <10%.

26. Prevention of HBV recurrence after liver transplantation All patients on the transplant waiting list with HBV related liver disease should be treated with NA Combination of hepatitis B immunoglobulin (HBIG) and a potent NA is recommended after liver transplantation for the prevention of HBV recurrence HBsAg-negative patients receiving liver from donors with evidence of past HBV infection (anti-HBc positive) are at risk of HBV recurrence and should receive antiviral prophylaxis with a NA

27. Patients undergoing immunosuppressive therapy or chemotherapy All candidates for chemotherapy and immunosuppressive therapy should be tested for HBV markers prior to immunosuppression Prophylaxis should be initiated at least one week before the start of immunosuppression in HBsAg-positive patients, and the same is likely true for HBsAg negative, anti-HBc-positive patients who require prophylaxis In general, antiviral therapy should be continued for at least 6 to 12 months after withdrawal of immunosuppression H ighly potent antiviral agents with a high barrier to resistance (e.g., TDF or entecavir) are the preferred agents suggested by current guidelines

28. Dialysis and renal transplant patients All dialysis and renal transplant recipients should be screened for HBV markers HBsAg -positive dialysis patients who require treatment should receive ETV or TAF All HBsAg -positive renal transplant recipients should receive ETV or TAF as prophylaxis or treatment HBsAg -negative, anti- HBc positive subjects should be monitored for HBV infection after renal transplantation

29. Extrahepatic manifestations Patients with replicative HBV infection and extrahepatic manifestations ( vasculitis , skin manifestations ( purpura ), polyarteritis nodosa , arthralgias , peripheral neuropathy and glomerulonephritis) should receive antiviral treatment with NA

30. Prevention Immunoprophylaxis against HBV can be by passive immunization using HBIG or active immunization using HBV vaccine HBV vaccines typically achieve an anti-HBs titer greater than 100 mIU / mL. Antibody titers greater than 100 mIU /mL confer 100% protection against HBV infection, and a lower antibody titer (up to 10 mIU /mL) is seroprotective in most instances. The typical vaccination schedule is 0, 1, and 6 months after birth For unvaccinated individuals the vaccination schedule is 0, 1, and 6 months as well

31. POST EXPOSURE PROPHYLAXIS

32. OVERVIEW OF HCV HCV is a hepacivirus of flaviviridae discovered in 1984. It is a 68 nm diameter , spherical and icosahedral in shape with a linear positive sense single stranded RNA genome encoding 10 viral proteins .

33. The viral genome of HCV codes for total 10 proteins , and out of these 3 are structural and 7 are non structural . Understanding these protein is important to understand the pathogenesis , new DAA’s action and resistance development in HCV . Structural proteins Core protein Key element to form viral nucleocaspid E1(envelop protein 1) E2(envelope protein 2) Forms non covalent complexes that takes part in receptor binding and fusion .

34. Non Structural Proteins NS 4(a and b) NS4B protein helps in formation of membranous web for making replication site for HCV NS3 NS3-4A(co factor NS4A) act as cleaver of polyprotein formed by the RNA of HCV to release monocomponent protein. NS5A Act as REPLICATION regulator c/a “REPLICASE FACTOR” NS5B It is the key enzyme for synthesizing RNA to produce “New virus copies”. P7 Act as a ion channel for virus. The new DAA’s (Direct Acting Antivirals) exclusively target NS3-4A protein NS5A protein NS5B protein

35. Initial assessment of subjects with HCV infection HCV markers Liver disease Marker A nti HCV Biochemical parameters: ALT H CV RNA Fibrosis markers: non-invasive markers of fibrosis ( elastography ) or liver biopsy HCV Genotype If the anti-HCV result is negative, then HCV RNA testing should be performed in patients with a recent exposure in case the anti-HCV result is falsely negative because of insufficient time for anti-HCV to develop or if the host is immunocompromised with failure to produce sufficient anti-HCV.

36. TREATMENT ALGORITHM FOR TREATMENT NAÏVE PATIENTS WITHOUT CIRRHOSIS

37. Treatment algorithm for treatment-naive adults with compensated cirrhosis.

38. RECOMMENDED DAA REGIMENS FOR DECOMPENSATED CIRRHOSIS

39. ACUTE HEPATITIS C A reasonable approach for managing acute hepatitis C is to monitor the serum HCV RNA for at least 12 to 16 weeks before DAA treatment is considered to allow adequate time for spontaneous clearance wherein DAA’s are initiated if spontaneous clearance is not achieved The same regimens used for chronic HCV infection are recommended in acute HCV infection

40. VIROLOGICAL RESPONSE Rapid virologic response (RVR)-negative HCV RNA level at treatment week 4) Complete early virologic response(SVR-12)- negative HCV RNA level at treatment week 12 The AASLD/Infectious Diseases Society of America (IDSA) Guidance recommends HCV RNA testing at treatment week 4, not to determine treatment stopping rules, but to ensure treatment adherence

41. TREATMENT GOAL Treatment of chronic HCV infection has two goal: To achieve sustained eradication of HCV (i.e., SVR), which is defined as the persistent absence of HCV RNA in serum 12 weeks after completing antiviral treatment. T o prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.

42. APPROVED ANTI VIRALS INTERFERON α 1( alfacon )was the first drug approved for hepatitis C. Pegylated IFN α 2A Pegylated IFN α 2B Ribavirin Before 2011, interferon and ribavirin were the standard of care therapies, but they offered rather low clinical effectiveness and caused serious side effects . The advent of DAAs opened an era to potentially cure HCV in most patients.

43. CLASSIFICATION OF DAA’s(FDA APPROVED) NS3-4A INHIBITORS ( poly protein cleavage inhibitors)- - previr’s Grazoprevir Glecaprevir Simeprevir Voxiprevir Paritaprevir (boosted with ritonavir) NS5A INHIBITORS ( inhibitor of replication complex formation and delivery of viral genome to viral assembly ) - - asvir’s Ledipasvir Ombipasvir Velpatasvir Elbasvir Daclatasvir Pibrentasvir L O V E Daclatasvir

44. 3. NS5B INHIBITOR ( competes with incoming nucleoside triphosphate interrupt RNA synthesis) – buvir’s Sofosbuvir (competitive nucleoside ) 4. NS5B INHIBITOR (non competitive non nucleoside inhibitor of RNA synthase NS5B site) – buvir’s Dasabuvir

45. SOFOSBUVIR Sofosbuvir is a pangenotypic NS5B nucleotide inhibitor that is administered as a single 400-mg tablet or as part of an FDC with other DAAs Dose reduction is recommended in patients with an estimated glomerular filtration rate (eGFR)less than 30 mL/min/1.73m2 Since it is transported by P- gp , sofosbuvir should not be co-administered with strong inducers of P- gp , such as rifampin, carbamazepine, phenytoin. Sofosbuvir is contraindicated in patients receiving amiodarone because severe and life-threatening bradycardia within hours to weeks of co-administration has been reported.

46. CONTRAINDICATIONS TO USE OF DAA’S 1. Early acute HCV infection 2. D ecompensated cirrhosis with a high MELD score in a patient waitlisted for Liver Transplantation There is in sufficient data regarding the safety of the new DAAs in pregnancy, and, therefore, they are not recommended during pregnancy.

47. PREGNANCY DAAs are not recommended during pregnancy C urrent recommendations are that HCV should be treated prior to pregnancy when possible to minimize any risk of vertical transmission. If this is not possible, then treatment should be initiated in the postpartum period. Short duration of treatment with the IFN-free DAA regimens (8 to 12 weeks for the majority of regimens)

48. HCV-HIV COINFECTION Patients with HCV-HIV coinfection are likely to progress more rapidly to cirrhosis than are HCV- monoinfected patients T reatment of HCV infection should always be considered in this group Daily daclatasvir plus sofosbuvir (400 mg), with or without ribavirin, is a recommended regimen when antiretroviral regimen changes cannot be made to accommodate alternative HCV direct-acting antiviral medications

49. PREVENTION OF HCV RECURRENCE FOLLOWING LIVER TRANSPLANTATION

50. HCV WITH CKD HCV itself can cause CKD as an extrahepatic complication of HCV infection T imely treatment of HCV infection is important to optimize outcomes in persons with CKD. In patients with stage 1 to 5 CKD, no dose modifications are required for any of the approved DAAs, and, therefore, DAA regimens should be chosen based on HCV genotype, fibrosis stage, and treatment history

51. NEW AGENTS UNDER DEVELOPMENT AND FUTURE TREATMENT POSSIBILITIES: Entry inhibitors: Myrcludex -B- Works by blocking or silencing NTCP receptor required by HBV and HDV to enter the hepatocyte 2. cccDNA Silencing - A number of enzymes, including zinc finger nucleases, have been shown to inhibit cccDNA conversion from relaxed circular DNA and to directly degrade and to epigenetically modify cccDNA . The CRISPR (clustered regularly interspaced short palindromic repeats)-associated 9 system (cas9) represents another group of cccDNA silencing molecules that can target and theoretically eliminate cccDNA from infected hepatocytes.

52. 3. Small Interfering RNA: Small interfering RNA (siRNA) are small molecules that bind to and silence HBV viral messenger RNA, thereby reducing translation of viral proteins 4. Core Protein Assembly Modulators : P rimary mechanism of action is prevention of HBV encapsidation and blockade of viral replication, thereby resulting in empty capsids that contain no viral genome. 5. HBsAg Release Inhibitors : HBsAg is thought to act to exhaust T cells, thereby leading to immune tolerance to the virus and evasion of immune attack. Therefore, significant reductions in HBsAg levels may restore host immunity to HBV

53. NEWER AGENTS UNDER DEVELOPMENT NS3/4A inhibitors Vedroprevir Danoprevir (restores insulin activity in pt with GT1 HCV) Narlaprevir Faldaprevir/ deleobuvir (non nucleoside combination) NS5A inhibitors Ruzasvir Samatasvir Ravidasvir NS5B inhibitors Deleobuvir Beclabuvir Mericitabine Tegobuvir

54. 4. E1/E2 and p7 inhibitors Adamantane Rimantadine Flunarizine 5. Immuno -stimulators and cellular protein inhibitors Alisporivir ( nonimmunesuppressive compound that targets the host protein cyclophilin A to block the peptidyl-prolyl cis /trans isomerase activity)