Diskusi Topik.pptx penanganan hepatitis b

hep b

1. DISKUSI TOPIK DIVISI GASTROENTERO-HEPATOLOGI Update Tatalaksana Hepatitis B Kronik Divisi Gastroentero-Hepatologi , Departmen Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Andalas RSUP Dr M Djamil , Padang Dipresentasikan oleh : dr. Rijalun Arridho 2150302229 August, 2024 1

2. 2 PNPK HEPATITIS B 2019

3. 3 Indikasi Terapi 1. Nilai HBV DNA serum 2. Status HBeAg 3. Nilai ALT 4. Derajat fibrosis Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

4. 4 Indikasi Terapi pada HBeAg P ositif Menteri Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. >8 KPa

5. 5 Indikasi Terapi pada HBeAg Negatif >8 KPa Menteri Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

6. 6 Indikasi Terapi pada HBeAg positif HBV DNA > 20.000 IU/mL dengan ALT >2x ULN HBV DNA > 20.000 IU/mL dengan ALT <2x ULN + inflamasi sedang-berat atau fibrosis signifikan HBV DNA <20.000 + inflamasi sedang-berat atau fibrosis signifikan Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

7. 7 Pilihan Terapi Golongan interferon : pegylated interferon alfa-2a dan alfa 2b Golongan analog nukleos (t) ida : lamivudin 100 mg, adefovir 10 mg, entecavir 0,5 mg, telbivudin 600 mg, dan tenofovir 300 mg Subkutan , 1x/ minggu ( maksimal 48 minggu ) Oral, 1x sehari , jangka panjang ( seumur hidup ) 1 2 Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

8. 8 Pilihan Terapi Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

9. 9 Rekomendasi Pilihan Terapi Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

10. 10 Pemantauan Terapi Nukleos (t) ida Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Secara umum minimal efek samping , namun perlu pemantauan fungsi ginjal setiap 3 bulan Pemeriksaan HBV DNA, anti HBe , dan ALT setiap 3-6 bulan untuk mengetahui kemungkinan resistensi Terapi seumur hidup harus dipertimbangkan

11. 11 Penghentian Terapi Analog Nukleosida Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. HBeAg positif tanpa sirosis : serokonversi HBeAg setelah terapi konsolidasi HBeAg positif dengan sirosis : terapi seumur hidup HBeAg negatif : terapi seumur hidup , pertimbangan dihentikan jika HBsAg loss / serokonversi HBsAg / HBV DNA tidak terdeteksi 2 tahun ( risiko kekambungan signifikan ), kemudian cek HBeAg , ALT dan HBV DNA tiap 3 bulan

12. 12 HBeAg negatif prediktor sirosis hati Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Pada HBeAg negatif , infeksi berapa pada fase replikasi rendah / non- replikatif atau pada fase reaktivasi Pada fase reaktivasi  anti Hbe positif , HBV DNA > 20.000, abnormalitas ALT persisten atau berulang , terjadi inflamasi sedang sd berat pada hati atau fibrosis  sehingga membutuhkan anti viral Pada fase non replikatif atau replikasi rendah  ALT persisten normal, HBsAg < 1000 IU/mL, HBV DNA < 2000 IU/mL, gambaran histologi kerusakan hati ringan  anti viral tidak direkomendasikan

13. 13 Kegagalan Terapi Analog Nukleosida Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Kegagalan terapi primer : evaluasi kepatuhan minum obat , ganti ke jenis obat lain seperti adefovir Respon virologis parsial : Lamivudin / telbivudin pada minggu ke 24 HBV DNA < 200 IU/mL atau adevofir pada minggu ke 48. Obat dapat diteruskan jika ada tren penurunan HBV DNA Virologic breakthrough dan resistensi

14. 14 Terapi pada Penyakit Hati Lanjut Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Insidensi sirosis pada HBeAg negatif lebih tinggi dibandingkan HBeAg positif Prediktor sirosis : usia , replikasi virus persisten , kosumsi alkohol , koinfeksi virus hepatitis C

15. 15 Terapi pada Sirosis Hati Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Terapi dengan interferon maupun nukleos (t) ida menurunkan risiko dekompensasi atau KHS dan meningkatkan harapan hidup pasien . IFN dan Peg-IFN aman dan efektif digunakan pada pasien hepatitis B dengan sirosis kompensata . Jika tidak berespon maka pemberian nukleos (t) ida dapat dipertimbangkan sebagai terapi jangka panjang Pemberian IFN merupakan kontraindikasi . Dapat diberikan golongan nukleos (t) ida . Stadium Kompensata Stadium Kompensata

16. 16 Koinfeksi Penyakit Koinfeksi HBV + HCV : direct acting antiviral (DAA) Koinfeksi HBV + HDV : Peg-IFN satu satunya obat yang efektif Koinfeksi HBV + HIV : Tenofovir dan lamivudin adalah terapi pilihan Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019. Infeksi HBV pada wanita hamil : dimulai pada trimester 3 pada HBV DNA > 20 IU/ mL. Dapat diberikan tenovofir , telbivudin . Peg IFN di kontraindikasikan

17. 17 Algoritma Imunoprofilaksis hepatitis B pada Bayi Baru Lahir Kementrian Kesehatan Republik Indonesia. PNPK Tatalaksana Hepatitis B. 2019.

18. 18 American Association for Study of Liver Disease (AASLD) 2016 & 2018 GUIDELINE

19. 19 Phases of CHB Infection Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84

20. 20 Burden of Disease Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84 Globally, an estimated 240 million person have CHB, highest Africa and Asia Globally, death from cirrhosis and HCC were estimated 310.000 and 340.000 per year. Screening, vaccination, monitor and treat complication and surveillance were important

21. 21 Host, viral, environtment factors associated with cirrhosis and HCC Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84

22. 22 Initial evaluation of HBsAg positive patient Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84

23. 23 Approved Antiviral Therapies in Adults and Children Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84

24. 24 Antiviral therapy Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84 The goals of antiviral treatment are to decrease the morbidity and mortality related to CHB. The achievement of a sustained suppression of HBV replication has been associated with normalization of serum ALT, loss of HBeAg with or without detection of (anti- HBe ), and improvement in liver histology Immunological cure may be defined by HBsAg loss and sustained HBV DNA suppression and a virological cure defined by eradication of virus, including the cccDNA form. The latter is not currently an attainable goal

25. 25 Antiviral therapy Terrault NA, Bzowej NH, Chang KM, Jwag KM, Hwang JP, Jonas MM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016;63(1):261-84 Overall, all NAs have an excellent safety profile across a wide spectrum of persons with CHB, including those with decompensated cirrhosis and transplant recipients For persons with HDV coinfection , the only effective treatment is pegylated interferon (Peg-IFN) For persons with HIV coinfection , treatment of HBV needs to be coordinated with HIV therapy given that several HBV drugs have anti-HIV activity ( tenofovir , entecavir , lamivudine, and telbivudine ). The best predictor of sustained remission off-treatment is HBsAg loss, but this is infrequently achieved with current therapies

26. 26 Treatment of Person with Immune Active CHB Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD recommends antiviral therapy for adults with immune-active CHB ( HBeAg negative or HBeAg positive) to decrease the risk of liver-related complications (1A) The AASLD recommends Peg-IFN, entecavir , or tenofovir (TDF) as preferred initial therapy for adults with immune-active CHB (1B) Immune-active CHB is defined by an elevation of ALT >2 ULN (33 U/L for male or 25 U/L for females) or evidence of significant histological disease plus elevated HBV DNA above 2,000 IU/mL ( HBeAg negative) or above 20,000 IU/mL ( HBeAg positive) Tenovofir alafenamide (TAF) or entecavir in patients with or at risk for renal dysfunction or bone disease. But TAF is not recommended if GFR <15 or on HD.

27. 27 Treatment of Person with Immune Active CHB Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 Additional factor included in the decision to treat person with immune active CHB but ALD < 2 ULN and HBV DNA <2000 IU/mL if HBeAg negatif or <20.000 IU/mL if HBeAg positif ) : Age >40 years Family history of cirrhosis or HCC Previous treatment history Presence of extrahepatic manifestation Presence of cirrhosis

28. 28 Treatment of Person with Immune Active CHB Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 Duration of therapy for NA-based therapy is variable and influenced by HBeAg status , duration of HBV DNA suppression, and presence of cirrhosis and/or decompensation . All NAs except TAF require dose adjustment in persons with creatinine clearance <50 mL/min. For patients treated with peg-IFN, 48 weeks’ duration is used in most studies and is preferred Treatment with antivirals does not eliminate the risk of HCC, and surveillance for HCC should continue in persons who are at risk

29. 29 Treatment of Immune-Tolerant Adults with CHB Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD suggests that ALT levels be tested at least every 6 months for adults with immune tolerant CHB to monitor for potential transition to immune-active or immune-inactive CHB The AASLD recommends against antiviral therapy for adults with immune-tolerant CHB (1A) The AASLD suggests antiviral therapy in the select group of adults > 40 years of age with normal ALT and elevated HBV DNA (1,000,000 IU/mL) and liver biopsy specimen showing significant necroinflammation or fibrosis

30. 30 Treatment of HBeAg -positive, immune active person with CHB who seroconvert to anti- Hbe on NA therapy Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD suggests that HBeAg -positive adults without cirrhosis but with CHB who seroconvert to anti- HBe on therapy discontinue NAs after a period of treatment consolidation The period of consolidation therapy generally involves treatment of persistently normal ALT levels and undetectable serum HBV DNA levels for at least 12 months When to stop the drug ?

31. 31 Treatment of HBeAg -negative, immune active CHB Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD suggests indefinite antiviral therapy When to stop the drug ?

32. 32 Treatment of HBeAg -negative, Normal ALT, and HBV DNA < 2000 I/mL Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 Antiviral therapy is not recommended Inactive chronic hepatitis B

33. 33 HBsAg positive with cirrhosis Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD recommends that HBsAg -positive adults with decompensated cirrhosis be treated with antiviral therapy indefinitely regardless of HBV DNA level , HBeAg status, or ALT level to decrease risk of worsening liver-related complications

34. 34 CHB in Pregnancy Terrault NA, McMahon Bj , Chang KM, Hwang JP, Jonas MM, Brown RS, et al. Update on prevention, diagnosis and treatment of chronic hepatitis B L AASLD 2018 hepatitis B guidance. Hepatology . 2018;67(4):1560-99 The AASLD suggests antiviral therapy to reduce the risk of perinatal transmission of HBV in HBsAg -positive pregnant women with an HBV DNA level >200,000 IU/mL The AASLD recommends against the use of antiviral therapy to reduce the risk of perinatal transmission of HBV in HBsAg -positive pregnant women with an HBV DNA level ≤200,000 IU/mL

35. 35 AASLD AND EASL TREATMENT ENDPOINT CONFERENCE 2022

36. 36 Introduction Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference FUNCTIONAL CURE for Chronic Hepatitis B (CHB) HBV Treatment Endpoint Conference Washington DC Academia Industry Regulatory agencies Int organization

37. 37 Primary Endpoint for Clinical Trials for Finite Treatment of CHB Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference Primary goal therapy for clinical trial, Preventing : Cirrhosis Hepatic failure HCC Liver related death Unfeasible Intermediet endpoints Biochemical (normalization of ALT level) Virological (HBV DNA < lower limit of quantitation) Serological ( HBsAg loss ± seroconvertion to anti- Hbs and HBeAg loss ± seroconversion to anti Hbe ) Histological (improvement inflamation and fibrosis)

38. 38 Primary Endpoint for Clinical Trials for Finite Treatment of CHB Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference Current therapies ( pegIFNa ) and Nas are not curative due to the persistence of cccDNA as a stable non integrated form of viral DNA in hepatocyte nucleus Challenge New finite duration therapies are needed , together with a scaling up of existing antiviral treatments , to reduce the enormous impact of CHB on global health, with >800,000 deaths annually The selection of the most appropriate endpoint for clinical trials evaluating new finite therapies is challenging.

39. 39 Definition of HBV cure and their redefinition Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference <10 IU/mL

40. 40 Risk reduction in low marker level Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference Lower HBsAg levels (<100 IU/mL) were associated with reduced HCC risk. The definition of partial cure using more established biomarkers of quantitative HBsAg ( q HBsAg ) <100 IU/mL and HBV DNA (<LLOQ) 24 weeks off therapy was suggested Eliminating cccDNA and integrated HBV DNA is unattainably high bar to achieve in current therapies. Moreever lack commercial and standarization assays quantifying it. A sustained reduction in HBsAg to low levels is, thus, a potentially clinically meaningful therapeutic endpoint .

41. 41 Novel Treatment Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference Small interfering RRNA ( siRNA ) and anti-sense oligonucleotides target all transcripts encoding HBsAg . Data from REEF-2 study reported that partial cure of NA and siRNA treatment reduced/delayed increased HBV DNA and ALT after stopping treatment Consensus stated that functional cure with the modification of HBV DNA from “TND” to <LLOQ, is still the recommended endpoint for clinical trials evaluating finite therapies for the treatment CHB Recommendations on the end-points of therapy will continue to evolve as new therapies able to target viral cccDNA , integrated HBV DNA, HBV RNA destabilization , and host targets are developed

42. 42 Primary endpoint for clinical trials for treatment of CHB Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference

43. 43 Define the role of biomarkers in phase II/III studies Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference

44. 44 HBV life cycle and drug targets Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference

45. 45 Management of on treatment and off treatment ALT flares and virological rebound Ghany MG, Buti M, Lampertico P, Lee HM. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D : Report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference

46. 46 EUROPEAN ASSOCIATION STUDY OF THE LIVER (EASL) 2017

47. 47 Assessment of chronic HBV infection based on liver marker European Association for the study of the liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. 2017;67:370-98.

48. 48 Algorithm for the management of HBV infection European Association for the study of the liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. 2017;67:370-98.

49. 49 Week 12 and 24 stopping rules for HBeAg positive and negative patient treated with PegIFN-alfa European Association for the study of the liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. 2017;67:370-98.