EBM

1. Reporter: R2 王人緯 Supervisor: MA 董淳武 2010/01/28 EBM

2. 情境

3. 李先生在3年前因為尿毒症狀與急性肺水腫開始接受規則的血液透析治療。原本對於自己慢性C型肝炎帶原的狀況也多不以為意，只是順從醫囑接受每個月肝功能檢測與定期每半年接受肝臟超音波的篩檢。但是從去年的8月到現在，每個月的肝功能檢測在AST和ALT (肝臟轉胺酶)部分均有明顯異常的現象，其數值都一直維持在70至100 U/L之間。他聽從查房主治醫師的建議去肝臟科門診求診，追蹤的超音波檢查並沒有發現肝臟硬化或是肝腫瘤的情形，所以門診醫師只建議他定期追蹤就好。但李先生真的很擔心，因為在他隔壁床的李媽媽於去年底才因慢性C型肝炎帶原併發肝癌去世，而李媽媽的每個月抽血也經常發現AST和ALT多有偏高的現象。李先生又聽說很多人因為C型肝炎久了產生肝硬化現象而造成腹水和食道靜脈瘤出血，為此他真的很害怕且煩惱。剛好健保局在去年10月公告要擴大B 、C肝炎藥物給付條件與延長治療的療程。所以李先生想知道，他是否可以符合健保的給付以接受C型肝炎的治療(干擾素治療加上抗病毒藥物)；以及接受這一項治療的好處和可能帶來的副作用或後遺症。

4. Question • Asking an answerable question • Search • Tracking down the best evidence • Appraisal • Critical appraisal • Practice • Integrating the appraisal with clinical experise and patient’s preference • Audit • Evaluation the effectiveness and efficiency in executing step 1-4 Five steps to practice EBM(Q-S-A-P-A)

5. The Question Formation Formulate the clinical question: In a hemodialysis patient with HCV infection, is the intervention of IFN/RBV treatment effective to viral eradication without massive adverse events compared to no treatment?

6. Question • Asking an answerable question • Search • Tracking down the best evidence • Appraisal • Critical appraisal • Practice • Integrating the appraisal with clinical experise and patient’s preference • Audit • Evaluation the effectiveness and efficiency in executing step 1-4 Five steps to practice EBM(Q-S-A-P-A)

11. Question • Asking an answerable question • Search • Tracking down the best evidence • Appraisal • Critical appraisal • Practice • Integrating the appraisal with clinical experise and patient’s preference • Audit • Evaluation the effectiveness and efficiency in executing step 1-4 Five steps to practice EBM(Q-S-A-P-A)

12. Critical Appraisal Skills Program (CASP) Validity (Reliability) 效度/信度 Can we believe it ? (研究方法的探討) Importance (Impact) 重要性 We believe it ! But does it matter? (研究結果的分析) Practice (Applicability) 臨床適用性 If we believe it - does it apply to our patients? (如何在臨床運用)

13. Oxford Center for Evidence-based Medicine Levels of Evidence (May 2001)

14. Guideline American Gastroenterological Association medical position statement on the management of hepatitis C Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 2006 Jan;130(1):225-30.

15. End-stage renal disease. Currently, ribavirin is contraindicated in patients with renal failure; however, clinical trials are in progress to assess the safety and efficacy of low-dose ribavirin combined with PEG-IFN. At present, the role of antiviral therapy in patients with end-stage renal disease remains undefined. For individual patients, the potential benefit of therapy should be weighed against the higher risk of toxicity, and treatment should be undertaken in centers with experienced clinicians, ideally in clinical trials. For PEG-IFN alfa-2a, a dose reduction from 180 to 135 micrograms is recommended by the manufacturer for patients with renal failure; for PEG-IFN alfa-2b, the manufacturer makes no specific recommendation about dose reduction for patients with renal failure, but 50% dose reductions are recommended for other clinical indications (e.g., hematologic). Patients with end-stage renal disease and chronic hepatitis C who are candidates for kidney transplantation should be evaluated for advanced hepatic fibrosis, which is associated with reduced graft and patient survival.

16. Guideline Diagnosis, management, and treatment of hepatitis C: an update Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009 Apr;49(4):1335-74.

17. Treatment of HCV in patients on dialysis may be considered with either standard interferon (2a or 2b) in a dose of 3 mU 3 times a week (t.i.w.) or reduced dose pegylated interferon 2a, 135 micrograms/week or 2b 1 microgram/kg/week. (Class IIa, level C) Ribavirin can be used in combination with interferon in a markedly reduced daily dose with careful monitoring for anemia and other adverse effects. (Class IIb, level C)

18. Level 1b

19. OBJECTIVES • The goal of the study was to determine the efficacy and safety of pegylated interferon a-2b in haemodialysis patients with chronic hepatitis C Method • Randomized clinical trials • Patient number: 16(HCV RNA positive by PCR and under H/D) • Randomized haemodialysis patients with chronic hepatitis C to 1.0 or 0.5 mg/kg of pegylated interferon a-2b subcutaneously, weekly for up to 48 weeks. End-points were sustained viral response and adverse events.

20. Inclusion criteria • Age >=18 y/o • Serum positive for HCV RNA by PCR • Liver biopsy within 36 months of inclusion confirming a pathological diagnosis of chronic hepatitis C • Compensated liver disease defined as absence of ascites, variceal bleeding, or encephalopathy and, PLT>90.000mm3 • Hb>=8.0g/dl • WBC>=2500/mm3 and neutrophil count >=1500/mm3 • Thyroid-stimulating hormone within normal limits or thyroid disease under control • Never treated with interferon before • Subjects were required to use two elective methods of contraception.

21. Exclusion criteria • Hypersensitivity to a-IFN • Any cause for chronic liver disease other than chronic hepatitis C • Evidence of decompensated liver disease such as a history of or presence of ascites due to liver disease • Any known history of active seizure disorders requiring medication, poorly controlled diabetes mellitus, serious pulmonary disease; systemic immunologically mediated diseases or any medical condition requiring, or likely to require during the course of the study, chronic systemic administration of steroids • Patients with evidence of cardiac ischemia, arrhythemia, heart failure, recent coronary surgery, poor controlled HTN, angina, or MI in previous 12 months • Ongoing substance abuse, such as alcohol (>80 g/day), intravenous drugs or inhaled drugs • Patients with history of organ transplantation on immunosuppression • Patients with untreated and uncontrolled depression, or a history of severe psychiatric disorder • Patient who were HIV positive

23. NNT: 5

24. Conclusion • The sustained response rate with pegylated interferon a-2b monotherapy in haemodialysis patients with chronic hepatitis C is low(22.2%, 0.0%), and also may be associated with a substantial number of adverse events.

25. Level 2a

26. Search strategy and data extraction • National Library of Medicine MEDLINE and manual searches were combined • The key-words ‘hepatitis C’, ‘interferon’,‘end-stage renal disease’, haemodialysis’ and‘dialysis’ were used. • General reviews, references from published clinical trials, letters to pharmacological companies, and Current Contents were also used. • All English and non-English articles were identified by a search from 1990 to July 2002. • Data extraction was conducted independently by two investigators (F.F. and V.D.), and consensus was achieved for all data. Criteria for inclusion • It had to be published as a peer-reviewed article, report the results of primary interferon monotherapy • Use the sustained virological response (SVR) as a clinical end-point. • Studies which included patients on maintenance haemodialysis or peritoneal dialysis were eligible.

30. The mean rate of SVR: 37%

31. The mean rate of drop-out: 17%

32. Conclusions • This meta-analysis shows that the tolerance to interferon is lower in dialysis than in non-uremic patients with chronic hepatitis C. However, more than one-third of haemodialysis patients with chronic hepatitis C have sustained virological response. Therapy should not be withheld from this group of patients, although their tolerance to side-effects may be less than that of non-uremic populations.

33. Level 2b

34. OBJECTIVES • A prospective multicentre study was initiated in HCV-infected haemodialysis patients to assess the tolerance and effecacy of a-2b interferon Method • Prospective study • Patient number: 37 • The dose of a-interferon was 3 million units three times weekly, to be reduced to 1.5 MU in case of side-effects. Tolerance was evaluated monthly; virological efficacy was evaluated by PCR. A liver biopsy was performed at month 18.

41. Conclusions • The study showed the poor tolerance of interferon in haemodialysis patients. Therefore this treatment should only be offered to patients who are waiting for kidney transplantation, to avoid the severe evolution of liver disease under immunosuppressive therapy, or in those with severe liver disease to limit development of cirrhosis. However, fairly high change of sustained response in patients reaching 12 month of treatment is noted.

42. Level 1b • Peg IFN α-2a is superior to standard IFN α-2a (48%vs 20%)in treatment-naïve dialysis patients with chronic hepatitis C not only because of virologic response but also adverse event (NNT: 4) • High pre-Rx HCV RNA level and failure to achieve RVR are predictors of poor response to IFN monotherapy

43. Level 2a • 28 clinical trials and 645 patients • The outcome measure: SVR and drop-out rate • SVR: 39% in conventional IFN; 31% in peg-IFN • Drop out rate: 19 % in conventional IFN; 27% in peg-IFN • A relationship between age and drop-out rate was found, even if no statistical significance was reached (P = 0.064)

44. Level 2a • 11 studies and 213 patients • The outcome measure: SVR and drop-out rate • The SVR for 3 MU IFN is 33% • IFN monotherapy is more effective in dialysis patient then in patient with normal renal function. IFN monotherapy is associated with more adverse events in dialysis patients.

45. Question • Asking an answerable question • Search • Tracking down the best evidence • Appraisal • Critical appraisal • Practice • Integrating the appraisal with clinical experise and patient’s preference • Audit • Evaluation the effectiveness and efficiency in executing step 1-4 Five steps to practice EBM(Q-S-A-P-A)

46. 到目前為止，在洗腎病人以干擾素治療C型肝炎應是可行的，但其成功率(以達到SVR的機會)與一般病人之差異仍待更進一步的研究; 唯洗腎病人使用干擾素治療的副作用發生機會較一般病人為大. 在洗腎病人的C型肝炎治療研究中，長效型干擾素與傳統干擾素孰優孰劣，目前仍無確切定論. 所搜尋到的資料中，並沒有IFN + RBV的相關研究. Conclusion

47. 詳細解釋目前以抗病毒藥物治療洗腎病人的C型肝炎之研究現況，並說明其副作用發生的機率較一般人為高；尤其李先生的AST/ALT均較正常值為高，副作用發生的機會可能更高，且達到無持續性病毒反應的效果機會可能偏低.詳細解釋目前以抗病毒藥物治療洗腎病人的C型肝炎之研究現況，並說明其副作用發生的機率較一般人為高；尤其李先生的AST/ALT均較正常值為高，副作用發生的機會可能更高，且達到無持續性病毒反應的效果機會可能偏低. • 是否需要治療，應依照病人之意願，善盡告知後同意. • 若李先生要求治療，到目前為止較被接受的干擾素劑量為: • Pegylated interferon 2a: 135 micrograms/week or 2b: 1 microgram/kg/week • Standard interferon (2a or 2b) in a dose of 3 mU 3 times a week • RBV的使用，目前仍無相關資料，不建議使用 Apply

48. Thanks for listening!