1. بنام خداوند مهربان

2. دکتر نرگس نجفی دانشیار دانشگاه

3. Case presentation: A 33-year-old man was diagnosed with hepatitis B virus (HBV) infection 4 months ago when his entire family was tested because an uncle living in Gorgan was found to have hepatocellular carcinoma (HCC). The patient had no remarkable medical problems and no symptoms of liver disease

4. Initial laboratory results : Platelet count: 180,000 cells/mm3 White blood cell count: 4600 cells/mm3 Hematocrit: 41% Alkaline phosphatase: 85 U/L Total bilirubin: 0.4 mg/dL Albumin: 4.6 g/L Globulin: 2.4 units International normalized ratio: 0.9 Alpha-fetoprotein: 4.0 ng/mL Thyroid-stimulating hormone: 4.0 IU/mL

5. laboratory results : HBV DNA: 3.7 x 10 8 IU/mL ALT: 55 IU/L AST: 45 IU/L HBV genotype C Hepatitis B e antigen (HBeAg) positive

6. physical examination the patient’s physical exam is normal and he undergoes imaging, which reveals a normal sized liver and no enlargement of the spleen.

7. QUESTION: Based on these laboratory results, how would you manage this patient? A. Begin treatment with an oral agent B. Monitor every 3-6 months to determine ALT rises C. Begin 48-week course of treatment with peginterferon alfa-2a D. liver biopsy

8. liver biopsy which reveals moderate chronic hepatitis, with an Ishak necro inflammatory score of 10 (out of 18) and a fibrosis score of 3 (out of 6).

9. QUESTION: Based on these laboratory and liver biopsy results, how would you manage this patient? A. Begin treatment with an oral agent B. Monitor every 3-6 months to determine ALT rises C. Begin 48-week course of treatment with peginterferon alfa-2a

10. Indications for treatment The indications for treatment are generally the same for both HBeAg-positive and HBeAg-negative CHB. This is based mainly on the combination of three criteria: Serum HBV DNA levels. Serum ALT levels. Severity of liver disease.

11. Indications for treatment Immunotolerant patients: HBeAg-positive patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level, without any evidence of liver disease and without a family history of HCC or cirrhosis, do not require immediate liver biopsy or therapy. Follow-up at least every 3–6 months is mandatory. Consider liver biopsy or even therapy in such patients over 30 years of age and/or with a family history of HCC or cirrhosis.

12. Selection of drug treatment with (PEG-)IFN or NA

13. Pre-treatment factors for IFN/PEG-IFN based treatment In HBeAg-positive CHB, predictors of anti-HBe seroconversion low viral load (HBVDNAbelow 2 108 IU/ml), high serum ALT levels (above 2–5 times ULN), HBV genotype A and B high activity scores on liver biopsy (at least A2)

14. laboratory results : HBV DNA: 3.7 x 10 8 IU/mL ALT: 55 IU/L AST: 45 IU/L HBV genotype C Hepatitis B e antigen (HBeAg) positive

15. Duration of treatment?

16. Case presentation: A 45-year-old woman with chronic hepatitis B is referred to you. Her hepatitis B virus (HBV) infection was diagnosed during her first pregnancy.

17. laboratory evaluations Hepatitis B surface antigen (HBsAg): positive Hepatitis B e antigen (HBeAg): negative HBV DNA: 1,650,000 IU/mL Alanine aminotransferase (ALT): 50 IU/L HBV genotype: D liver biopsy and the results indicate moderate (Metavir stage 2-3) fibrosis.

18. QUESTION: What type/duration of regimen would you recommend for initial therapy? A. Nucleos(t)ide analogue monotherapy for an indefinite duration B. Combination nucleos(t)ide analogue therapy for an indefinite duration C. Peginterferon alfa-2a for 48 weeks

19. Decision making for treatment Patients with obviously active CHB: HBeAg-positive and HBeAg-negative patients with ALT above 2 times ULN and serum HBV DNA above 20,000 IU/ml may start treatment even without a liver biopsy (B1). In such patients, liver biopsy may provide additional useful information, but it does not usually change the decision for treatment. A non-invasive method for the estimation of the extent of fibrosis and most importantly to confirm or rule out cirrhosis is extremely useful in patients who start treatment without liver biopsy (B1).

20. Selection of drug Peginterferon alfa-2a vs Nucleos(t)ides as First-line Therapy

21. Selection of drug efficacy (and durability of response), tolerability, risk of resistance, duration of treatment, mode of administration

22. Selection of drug Other factors that may influence the choice among the 5 available oral nucleos(t)ide analogues include pregnancy (or potential pregnancy), presence of coinfections comorbidities, schedule/food restrictions, and cost

23. Selection of drug peginterferon alfa-2a therapy is restricted to a limited duration (typically 48 weeks) whereas nucleos(t)ide analogue therapy can be, and often is, prolonged over long or indefinite time periods in HBeAg-negative patients

24. Drugs Drugs available for the treatment of CHB include IFN, PEG-IFN and six NAs. NAs for HBV therapy can be classified into nucleosides (lamivudine, telbivudine, emtricitabine, entecavir) and nucleotides (adefovir and tenofovir).

25. NAs Lamivudine is an inexpensive agent, but engenders very high rates of resistance with long-term monotherapy Adefovir is less efficacious and more expensive than tenofovir, engendering higher rates of resistance

26. NAs Telbivudine is a potent inhibitor of HBV replication, but, lower barrier to resistance, high incidence of resistance has been observed in patients with high baseline HBV DNA levels

27. NAs Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance Thus, they can be confidently used as first-line monotherapies

28. Selection of drug HBV genotype has been found to strongly correlate with sustained virologic response to interferon in both HBeAg-positive and HBeAg-negative hepatitis

29. Selection of drug The lowest rates of sustained virologic response with interferon alfa-2b have been shown to occur in HBeAg-negative patients infected with genotype D and high baseline viral loads.

30. Factors in Selecting an Oral Nucleos(t)ide Analogue–Based Regimen for Initial Therapy Among the 5 nucleos(t)ide analogues approved for the treatment of chronic HBV infection, only entecavir and tenofovir are the recommended agents for initial therapy in HBeAg-negative patients

31. Selection of Low baseline HBV DNA level (< 2 x 10 4 IU/mL) has been identified as a more consistent predictor of virologic response for agents such as lamivudine, adefovir, and telbivudine.

32. Selection of drug It has been suggested that for the more potent nucleos(t)ide analogues, baseline HBV DNA does not effectively predict the likelihood of achieving and maintaining undetectable HBV DNA

33. Selection of drug HBV genotype does not appear to influence the response to any nucleos(t)ide analogues

34. Selection of drug most clinical studies to date have not demonstrated improved outcomes with combination therapy vs monotherapy for the initial treatment of patients with compensated chronic HBV infection

35. Goal of therapy The goal of therapy for chronic HBV infection in both HBeAg-positive and HBeAg-negative patients is long- term virologic suppression without drug resistance to prevent or reduce the risk of progressive liver disease.

36. Goal of therapy Secondary goals of therapy in HBeAg-negative patients include sustained biochemical response (ALT normalization) and HBsAg loss or seroconversion the latter representing the ultimate indication of therapeutic success and possibly disease cure.

38. References: AASLD Guidelines for Treatment of Chronic Hepatitis B 2015 EASL Recommendations on Treatment of Hepatitis B 2012 Principles and practice of infectious diseases. Mandell 2015