HBV Guidelines and Cases Presentation

1. HBV Guidelines and Cases Presentation Prof. GamalEsmat Prof. Hepatology &Vice President of Cairo University, Egypt Member of WHO Strategic Committee for Viral Hepatitis www.gamalesmat.com

2. A case study:“You are a carrier: be happy!!”

3. 21 year male has a history of dental extraction since 2 years. He was told that he has HBsAg +ve before traveling to work aboard. He is Asymptomatic.

4. What is the next step? • Assurance: A Benign disease. Needs no treatment. Be happy! • Fruther investigations

5. His liver function were completely within normal range (ALT=37/40)His Abdominal Ultrasound was also normal

6. What is next step? • Assurance : you are OK. No treatment. Be Happy. • Further investigations.

7. HBeAg is negative

8. Next Step • Assurance: • No Active Disease. BE Happy !! • Further investigations

9. HBV - DNA - ve, 41 28 % 26 % HBV - DNA + ve, 103 72 % 66 % HBeAg+ve n=12 8% HBeAg-ve n=144 92% HBeAg-negative CHBEgypt156 HBsAg+ve CAHNLI, Unpublished, 2004 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

10. Further Investigations • Anti HBe Positive • Anti Delta IgG Negative • HB DNA 3000 IU/(15000 Copies)

11. Next Step • Assurance: you have a mild disease just follow – up. Need No Treatment. • Further investigations.

12. Ministry Of Health Regulations For Management of HBV in Adults Inclusion criteria for assessment Age > 18 years HBsAg: (+ve) HBV DNA (+ve)

13. Indication of Treatment • Treat if HBV >2000 IU + elevation of liver enzymes. • Follow up if HBV <2000 IU + normal liver enzymes. • Grey zone do liver biopsy

14. Liver Biopsy: showed • HAI-8 and F-2 • HBsAg +ve • HBcAg +ve

15. Liver biopsy : METAVIR scoring system F3 F4 F1 F2 From Z. Goodman

16. Liver biopsy(Indications) • HBV DNA > 2000 IU/ML with persistently normal enzymes . • HBV DNA < 2000 IU/ML with persistently elevated enzymes . • Patients < 2000 IU/ML with normal enzymes who show clinical evidence of liver disease or have a family history of HCC Treatment is recommended for those with >A1 and / or >F1 on the Metavir score

17. What is the next step? • Lamivudine • New oral antiviral therapy • Pegylated interferon • Combination

18. Treatment Landscape • Treatment has advanced dramatically due to the introduction of new agents with different safety, efficacy, and resistance profiles Nucleoside Analogue Nucleotide Analogue Cytokines Interferon (1992) Lamivudine (1999) Entecavir (2005) Telbuvidine (2006) Adefovir dipivoxil (2003) Tenofovir (2008) Peg Interferon a-2a (2005)

19. Medications • All Naïve patients are candidates for the most potent drugs Entecavir 0.5 or Tenofovir 300 mg as a first line therapy. Entecavir 0.5 mg O.D or Tenofovir 300mg O.D.

21. Tenofovir is preferred in: • patients who received lamivudine previously • young women who plan to start a family in next few years • patients who want more flexibility with regard to the time of day at which they take their medicine Entecavir is preferred in: • older patients • patients with medical conditions that increase risk of renal failure

22. Percent HBeAg response irrespective of treatment assignment (pegylated interferon/placebo vs pegylated interferon/LAM). Pegylated InterferonEffect of Genotype • A large multicenter study of 52 weeks of pegylated interferon alfa-2b, alone or in combination with LAM, according to genotype: • HBeAg-positive patients with genotype A responded significantly more frequently than those with genotypes B, C, or D in descending order.

23. Pegylated Interfon • Poor response in Egyptian patients with predominant Genotype D. • HbeAg positive patients with high liver enzymes could be offered a chance of treatment with peg Inf alfa for 24 weeks. • Seroconversion to HBeAb →continue for 48 wks • No seroconversion →stop ttt and shift to oral antiviral therapy according to previous guidelines

24. For Patients already on treatment • Chronic patients responding on regular Lamivudine treatment (undetectable HBV DNA) →continue treatment and HBV PCR every 3 to 6 months. • Patients on combined LAM & Adefovir → continue treatment or shift to Tenofovir 300 mg • Newly developed resistance → Shift to Tenofovir 300 mg O.D.

25. Immuntolerant cases • Young patients under 40 years of age who are HBeAg positive ,with high viral load and persistently normal enzymes are not candidates for immediate liver biopsy or treatment. • Follow up is mandatory every 3- 6 months by liver profile and every 6-12 months HBeAg . • Consider liver biopsy with fluctuating ALT levels or a positive family history of HCC .

26. Special Groups I) Compensated Cirrhosis: Naive Cirrhotic patients with any detectable level of HBV DNA should receive Entecavir 0.5 mg or Tenofovir 300mg. • II)Decompensated Cirrhosis: • Entecavir 1 mg may be appropriate. The dose of all NA,s needs to be adjusted in patients with low creatinine clearance (< 50ml/min) • lll)Renal Insufficiency: • Entecavir preferred with dose adjustments according to creatinine clearance.

27. Pregnancy For mothers: - All pregnant females should be screened for HBsAg - Newly diagnosed pregnant women in the last trimester showing an HBV DNA level > 100.000 IU/ML are candidates for Lamivudine 100 mg or Tenofovir 300 mg starting last trimester and for 3 months after delivery to decrease chance of new-born infection . Re-evaluate the condition after 3 months of delivery and consider treatment according to the previous guidelines

28. Pregnancy • For newborns: • HB Ig and HBV vaccine first (birth) dose for the baby in the first 6-12 hours after delivery. • Birth dose vaccination is recommended for all newborns.

29. Females who become pregnant while on treatment • On Lamivudinemonotherapy: Continue on treatment • On Other lines of treatment : shift to class B drug (Tenofovir 300 mg O.D.)

30. HBV/HDV Coinfection • Peg –INF is the only effective drug against HDV. • Efficacy of Peg –INF is assessed during treatment after 3-6 months by measuring HDV RNA levels. • Optimal duration of therapy is not well defined but therapy for at least 72 wks . • NAs have no impact on HDV replication and related disease. • Refer the patient to a specialized HBV center.

31. Acute HBV • Spontaneous recovery in more than 95% of cases and seroconversion to anti HBs without antiviral therapy. Supportive management and close monitoring for early identification of fulminant hepatitis or liver cell failure • Fulminant or impending liver cell failure: Entecavir 0.5 mg during the condition and for at least 6 months after seroconversion to anti HBs or for at least 12 months after seroconversion to anti HBe without HBs Ag loss

32. Dialysis and Renal patients • All renal patients should be screened for HBV . • Seronegative patients should be vaccinated. • Entecavir is preferred for treatment. • All drugs should be dose adjusted according to creatinine clearance.

33. HBV/HCV Co infection -Treat predominant virus according to PCR level. -Patients fulfilling the inclusion criteria for HBV treatment and have co-infection with active HCV (HCV RNA +ve by quantitative PCR) Monitoring for HBV is performed every 3-6 months. Reassessment of the condition after termination of the course and starting oral HBV treatment if needed. . Peg IFN + Ribavirin

34. Vaccination -Mass vaccination is recommended. -Vaccination is highly recommended for: Health care workers Close contacts of viremic patients Chronic renal failure patients before they start renal dialysis. Chronic hepatitis C patients. Immunosupressed patients. Multitransfused individuals

35. Follow up Follow up visits (every 2-3 months)for receiving medications & follow up for side effects and relapsing symptoms. Checking liver enzymes every 3 months. Serum creatinine is done every 3 months in those receiving Adefovir. For Tenofovir in addition monitor creat.clearance and serum phosphate for risk of renal impairement and osteomalacia. Liver function tests, complete blood count, A.F.P., Abdominal U/S & HBV/DNA by PCR quantitative is done every 6 months

36. Immunosupressed Patients • All candidates for chemotherapy and immunosuppressive therapy should be screened for HBsAg and anti HBcAb prior to initiation of treatment • Vaccination is mandatory for seronegative cases • HBsAg positive patients with any detectable level of viremia should receive NA during therapy and for 6 months after cessation of therapy

37. Immunosupressed Patients • Patients with high HBV DNA level should receive NA with high viral potency according to guidelines. • HBsAg neg patients with positive anti- HBc antibodies should be tested for HBV DNA. Patients with detectable viremia should be treated as HBsAg positive cases. • Follow up of cases with undetectable viremia every 1-2 months during treatment by liver enzymes and HBV DNA.

38. Case 2

39. A 30 years old female patient presented with easy fatigability and right hypochondrial pain. CBC : Normal . • ALT: 80/40 • HBsAg : +ve • HBeAg: -ve • Anti HCV: - ve • HBV- DNA: 2500 IU/ml

40. Fibroscan F2 • Does this patient needs treatment?

41. Patient received mono therapy in the form of lamivudine. After 6 months of therapy her ALT normalized and her HBV-DNA decreased to 200 IU/ml. • What are the goals for treatment of HBV? • What is the end point in treatment of HBV?

42. goals for treatment of HBV • The goal of therapy for hepatitis B is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death. This goal can be achieved if HBV replication can be suppressed in a sustained manner, the accompanying reduction in histological activity of chronic hepatitis lessening the risk of cirrhosis and decreasing the risk of HCC in non-cirrhotic patients and probably also, but to a lesser extent, in cirrhotic patients. However, HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.

43. Higher viral loadsassociated with long-term complications .04 >106c/ml 14 12 ≥106c/ml .03 105-106c/ml 10 Cumulative incidence of cirrhosis% 105-106c/ml Cumulative incidence of HCC % 8 .02 6 104-105c/ml 4 104-105c/ml .01 300-104c/ml 300-104cml 2 <300 c/ml < 300c/ml 0 11 12 10 13 2 6 8 1 3 7 9 4 5 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of follow-up Year of follow-up Progression to Cirrhosis Progression to HCC Iloeje UH et al. Gastroenterology 2006; 130: 678–86. Chen CJ et al. JAMA 2006; 295: 65-73

44. End point in treatment of HBV • Therapy must reduce HBV DNA to as low a level as possible, ideally below the lower limit of detection of real-time PCR assays (10–15 IU/ml), to ensure a degree of virological suppression that will then lead to biochemical remission, histological improvement and prevention of complications.

45. End point in treatment of HBV (cont.) • Sustained HBV DNA reduction to undetectable levels is necessary to reduce the risk of resistance to NUCs. It also increases the chance of HBeseroconversion in HBeAg-positive patients and the possibility of HBsAg loss on the mid to long term in HBeAg-positive and HBeAg-negative patients.

46. End point in treatment of HBV (cont.) • In HBeAg-positive and HBeAg-negative patients, the ideal end-point of therapy is sustained HBsAg loss with or without seroconversion to anti-HBs. This is associated with a complete and definitive remission of the activity of chronic hepatitis B and an improved long-term outcome. (2) In HBeAg-positive patients, durable HBeseroconversionis a satisfactory end-point because it has been shown to be associated with improved prognosis. (3) In HBeAg-negative and in In HBeAg-positive patients who do not achieve HBeseroconversion, and patients, a maintained undetectable HBV DNA level on treatment with NUCs.

47. One year after the start of treatment the patients HBV DNA started to increase by more than one log while her ALT levels are still normal in spite of her compliance to treatment. • Shall we replace lamivudine or add another drug?

48. Patient stopped treatment 3 years later after having persistent normal ALT and undetectable HBV DNA for 2 years while her HBsAg was still + ve. The patient got married and pregnant. • Does she need to restart therapy? • What precautions to be taken for the new born?

49. Guidelines for mang. of pregnant females with HBV • Lamivudine, adefovir and entecavir are listed by the FDA as pregnancy category C drugs, and telbivudine and tenofovir as category B drugs. These classifications are based on the risk of teratogenicity in preclinical evaluation.

50. Guidelines for mang. of pregnant females with HBV • Recent reports suggest that lamivudine therapy during the last trimester of pregnancy in pregnant women with high levels of viremia reduces the risk of intra-uterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination. • HBV-infected women should be monitored closely after delivery as exacerbations of chronic hepatitis B may occur J Viral Hepat 2008;15:37–41