약제 내성 만성 B형 간염 환자에서 S202, M250 엔테카비어 내성이 테노포비어 근간 구제 요법의 바이러스 반응에 미치는 영향
Entecavir Resistance at rtS202, rtM250 May Cause Poor Viral Response to Tenofovir-based Rescue Therapy in Chronic Hepatitis B
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
목적: 만성 B형 간염 치료에서 장기적인 항바이러스제 치료는 약제 내성 발현을 유도할 수 있다. 이번 연구는 다약제내성 및 기존 약제 내성에 대한 구제 요법에 부분 바이러스반응을 보이는 만성 B형 간염 환자를 대상으로 테노포비어근간 구제요법의 효과를 분석하고자 하였다. 방법: 총 54명의 다약제 내성 환자를 대상으로 후향적 분석을 시행하였다. 결과: 대상 환자는 26가지의 다양한 변이를 가지고 있었고, 76%가 1년 내에 완전 바이러스 반응을 보였으며, 다변량분석에서 치료 전 혈청 HBV-DNA 값이 20,000 IU/mL, HBeAg 음성은 완전 바이러스 반응을 보이는 예측인자였다. 흥미롭게도 S202 위치의 변이 여부가 바이러스 반응과 관련이 있었다. 결론: 다약제 내성 및 기존 약제 내성에 대해 부분 바이러스 반응을 보이는 만성 B형 간염 환자에서 치료 전 낮은HBV-DNA 수치, HBeAg 음성 여부, S202 변이가 없을 때 완전 바이러스 반응을 유도하는 경항을 보였다.
Abstract
Background/Aims: Long-term use of nucleos(t)ide analogues (NA) may lead to genotypic and/or phenotypic resistance of the hepatitis B virus (HBV). We investigated the efficacy of tenofovir-based rescue therapy in chronic hepatitis B (CHB) patients with newly developed genotypic resistance to prior NAs or partial virologic response to sequential rescue therapies. Methods: Fifty-four CHB patients were included retrospectively. The patients were treated with tenofovir alone or combined with lamivudine or entecavir. Results: There were 26 forms of genotypic resistance at enrollment. The median amount of serum HBV-DNA was 18,438 IU/mL and 83% of samples were positive for hepatitis B e antigen (HBeAg). Serum HBV-DNA was undetectable in 50%, 61%, and 76% of the patients at 3, 6, and 12 months, respectively. In multivariate analysis, HBV-DNA < 20,000 IU/mL and negative HBeAg at baseline were independent predictors of negativity for serum HBV-DNA. Interestingly, the rtS202 mutation tended to be associated with an unfavorable response. Other clinical variables and viral resistance genotypes showed non-significant viral response. Conclusions: Lower serum HBV-DNA, negative HBeAg and lack of rtS202G mutations at baseline may predict a favorable response to tenofovir-based rescue therapies in CHB patients with newly developed genotypic resistance to prior NAs or a partial virologic response to sequential rescue therapies.
참고문헌 (28)
- European Association for the Study of the Liver, "EASL Clinical Practice Guidelines: management of chronic hepatitis B", J Hepatol, 50, pp.227~242 (2009)
- Lok AS, "Chronic hepatitis B: update 2009", Hepatology, 50, pp.661~662 (2009)
- Liaw YF, "Hepatitis B virus replication and liver disease progression:the impact of antiviral therapy", Antivir Ther, 11, pp.669~679 (2006)
- Di Marco V, "Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine", Hepatology, 40, pp.883~891 (2004)
- Papatheodoridis GV, "Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine", Hepatology, 42, pp.121~129 (2005)
- Chang TT, "Long-term entecavir therapy results in the reversal of fibrosis", cirrhosis and continued histological improvement in patients with chronic hepatitis B, 2010, pp.52, 886~893
- Ghany MG, "Antiviral resistance and hepatitis B therapy", Hepatology, 49(5 Suppl), pp.S174~S184 (2009)
- Lok AS, "Antiviral drug-resistance HBV: standardization of nomenclature and assays and recommendations for management", Hepatology, 46, pp.254~265 (2007)
- Marcellin P, "Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B", N Engl J Med, 359, pp.2442~2455 (2008)
- Patterson SJ, "Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B", Gut, 60, pp.247~254 (2011)
- 이초이, "Efficacy and Safety of Tenofovir-Based Rescue Therapy for Chronic Hepatitis B Patients with Previous Nucleo(s", t)ide Treatment Failure, 2014, pp.8(1), 64~69[DOI]
- Lee YB, "Efficacy of entecavir-tenofovir combination therapy for chronic hepatitis B patients with multidrug-resistant strains", Antimicrob Agents Chemother, 58, pp.6710~6716 (2014)
- Lee YB, "Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in lamivudine-resistant chronic hepatitis B", Antimicrob Agents Chemother, 59, pp.972~978 (2015)
- Young-Suk Lim, "Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial", Gut (2015), BMJ[DOI]
- Young-Suk Lim, "Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial", Gut (2015), BMJ[DOI]
- 김효진, "Long-term efficacy of tenofovir disoproxil fumarate therapy after multiple nucleos(t)ide analogue failure in chronic hepatitis B patients", The Korean Journal of Internal Medicine, 30(1), pp.32~41 (2015), 대한내과학회[DOI]
- Qi X, "In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents", Antivir Ther, 12, pp.355~362 (2007)
- Lau GK, "Peginterferin a-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B", N Engl J Med, 352, pp.2682~2695 (2005)
- Janssen HL, "Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomized trial", Lancet, 365, pp.123~129 (2005)
- Mammeja-Marin H, "Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature", Hepatology, 37, pp.1309~1319 (2003)
- Perrillo RP, "Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B", Hepatology, 36, pp.186~194 (2002)
- Zeuzem S, "Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B", J Hepatol, 51, pp.11~20 (2009)
- Da Silva LC, "Predictive factors for response to lamivudine in chronic hepatitis B", Rev Inst Med Trop Sao Paulo, 42, pp.189~196 (2000)
- Da Silve LC, "Simultaneous quantitation of serum HBV DNA and HBeAg can distinguish between slow and fast viral responses to antiviral therapy in patients with chronic hepatitis B", Rev Inst Med Trop Sao Paulo, 51, pp.261~268 (2009)
- Ann W. Walsh, "Mechanistic Characterization and Molecular Modeling of Hepatitis B Virus Polymerase Resistance to Entecavir", PLoS ONE, 5(2), pp.e9195~ (2010), Public Library of Science (PLoS)[DOI]
- Tenney DJ, "Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine", Antimicrob Agents Chemother, 48, pp.3498~3507 (2004)
- Tenney DJ, "Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside naïve patients is rare through 5 years of therapy", Hepatology, 49, pp.1503~1514 (2009)
- Baldick CJ, "Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance", Hepatology, 47, pp.1473~1482 (2008)