LiverTODAY. EndoTODAY 이준행

[Dr. Sinn's LiverTODAY 022 - HCV 항바이러스 치료 후 간암 검진]

C형 간염 치료가 아주 쉽고 효과적이 되면서, C형 간염에서 치료된 분들이 많아지고 있습니다. AGA에서 발빠르게 expert review를 발표하였습니다.

American Gastroenterological Association Institute Clinical Practice Update-Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection Gastroenterology 2017

SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored vs discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic hepatitis C virus who have achieved SVR.

흥미로운 것은 best practice advice (BPA) 라고 제시한 11개 항목입니다.

BPA 1: SVR should be confirmed by undetectable HCV RNA at 12 wk after completion of an all-oral DAA treatment regimen.

BPA 2: Routine confirmation of SVR at 48 wk post end of treatment is recommended. Testing for HCV RNA at 24 wk post treatment should be considered on an individual patient basis.

BPA 3: Routine testing for HCV RNA beyond 48 wk after end of treatment to evaluate for late virologic relapse is not supported by available evidence; periodic testing for HCV RNA is recommended for patients with ongoing risk factors for reinfection.

BPA 4: Surveillance for HCC with liver imaging ± serum AFP should be pursued twice annually for an indefinite duration in all patients with stage 3 fibrosis or liver cirrhosis post-SVR.

BPA 5: Surveillance for HCC is not recommended for patients with stages 0-2 fibrosis post-SVR.

BPA 6: Intensification of HCC screening frequency in the immediate post-SVR context is not currently recommended.

BPA 7: Initial endoscopic screening for esophagogastric varices is recommended for all patients with liver cirrhosis, independent of SVR.

BPA 8: Repeat endoscopic screening should be pursued for cirrhotic patients post-SVR at 2-3 y if no varices or small varices were identified on initial screening examination.

BPA 9: If no varices are identified on endoscopy 2-3 y post-SVR, cessation of further endoscopic screening can be considered on an individual patient basis if there are no risk factors for progressive cirrhosis.

BPA 10: Fibrosis assessment post-SVR with noninvasive tools, such as liver elastography, can be considered on an individual patient basis to assess for interval fibrosis progression or regression to guide clinical management, although improved fibrosis measurements should not alter the frequency of HCC surveillance at the present time.

BPA 11: Patients who have achieved SVR should be counseled regarding sources of liver injury, which can independently contribute to liver fibrosis progression, including alcohol, fatty liver, and other potential hepatotoxins, and should be evaluated for these and other sources of liver injury if serum levels of liver enzymes are elevated.

[신동현 교수님 comment]

BPA 1. SVR 확인을 12주째 하는 것으로 충분하다는 것입니다(동의)

BPA 2. 1년뒤에는 한번정도 SVR이 유지되는지 확인해 보자는 것입니다(동의)

BPA 7-9. 우리나라에서 내시경은 정맥류만을 보려고 하는 것은 아니니, 그대로 적용하긴 어려울 것 같습니다(개인의견) --> 우리나라에서 무증상 성인, EGD recommendation (for EGC surveillance??) 은 어떻게 되는지 모르겠지만, biannual recommendation이라면 BPS 7-9는 무시해도 될 거 같습니다.

BPA 11. SVR 후에도 다른 간질환 위험인자가 있는지 살펴보고 관리해야 한다는 것입니다(동의).

BPA 4,5. SVR 이후에도 HCC 환자들이 있으니, stage 3 fibrosis or cirrhosis는 간암 선별검사를 해야 한다는 것입니다 (동의). --> post-SVR stage 0-2 fibrosis가 있는 사람은 간암 선별검사 안해도 된다는 것입니다(추가 의견)

BPA 10. Biopsy결과가 없을 때는 non-invasive 한 fibrosis assessment를 고려해 볼 수 있다는 것입니다(추가 의견) Non-invasive tool 중 가장 널리 사용되는 fibroscan관련 Review의 내용을 옮깁니다.

Sultanik et al reported that in a cohort of 341 patients with confirmed HCV cirrhosis, 45 (13%) of whom achieved SVR, liver stiffness measurements by TE were <12.5 kPa in three-fourths of those with SVR. Utilizing a threshold of 12.5 kPa, the area under the receiver operating characteristic curve was 0.66 for HCC in patients with SVR. Of 4 patients with HCC, 2 of 4 had elastography scores <12 kPa post-SVR. Based on their cumulative data, the authors cautioned against performing liver stiffness measurements to follow regression of fibrosis or cirrhosis. A study from Taiwan of 278 patients with SVR with a median follow-up period of 7.6 years, comprised of both non-cirrhotic and cirrhotic patients, showed a significantly greater risk of HCC with TE score >12 kPa. However, HCC also occurred with post-SVR scores <12 kPa, including patients with pretreatment scores either > or <12 kPa. At present, there is no reliable elastography score below which clinicians can confirm an absence of HCC risk with sufficient confidence to warrant discontinuation of surveillance.
The same conclusion can be derived from available studies on noninvasive blood or serum markers that assess fibrosis. Such markers often improve after SVR, and have correlated with risk of HCC in some studies, including a study in which the Forns index, but not FIB-4 index or aspartate aminotransferase to platelet ratio index, at follow-up week 24 correlated with long-term HCC risk. In a particularly long-term follow-up study spanning a 10-year period, FIB-4 index and aspartate aminotransferase to platelet ratio index scores declined substantially in patients with SVR and were significantly lower than in untreated patients or those with treatment failure, but no correlations with HCC were drawn.

Review에 소개 되지 않았지만^^, 저희 group도 non-invasive tool인 APRI의 유용성을 분석하여 보고한 바 있습니다 (Gut Liver 2016). 이 연구분석에서는 치료전 APRI가, 치료후 APRI보다 더 감별을 잘하는 것으로 확인되었습니다. 치료전 APRI가 높은 사람이, 치료 후 APRI가 좋아져도 적지만 간암 위험이 있는 것으로 나왔습니다. 치료전에 어느정도 fibrosis가 있었던 사람은 치료 후 fibrosis marker가 호전되어도 조심해야 합니다.

BPA5번, 즉 "Surveillance for HCC is not recommended for patients with stages 0-2 fibrosis post-SVR", 를 임상에서 실제로 적용하는 것은 주의해야 할 것 같습니다. 우리나라에서 간조직검사 후 치료한 경우는 거의 없습니다. 따라서 치료 전 fibrosis stage를 정확히 알 수 있는 경우는 매우 드뭅니다. Non-invasive predictors들은 정확도가 떨어집니다. C형 간염 환자들은 SVR후에도 정기적으로 monitoring을 하는 것이 안전할 것 같습니다.

[References]

1) EsoTODAY - Esophageal diseases

2) SmallTODAY - Small bowel diseases

3) ColonTODAY - Colorectal diseases

4) Dr. Sinn's LiverTODAY - Liver diseases