今日の臨床サポート

B型肝炎(治療)

著者: 柘植雅貴1) 広島大学 自然科学研究支援開発センター

著者: 茶山一彰2) 広島大学大学院 医系科学研究科 医療イノベーション共同研究講座

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/07/28
患者向け説明資料

概要・推奨   

  1. 非活動性キャリアであっても、肝細胞癌を発症することがあるため、定期的な経過観察が必要である(推奨度2)。
  1. インターフェロンの治療期間は24~48週間であるが、有効性(HBV DNA低下、ALT値正常化)は長期投与例で高く、ペグインターフェロン治療では48週間投与を基本とする(推奨度1)。
  1. B型慢性肝炎に対して、ペグインターフェロン治療を行うことにより、HBV DNAの減少やALTの正常化が得られるだけでなく、他のインターフェロンに比べ、高率にHBsのクリアランスが得られる可能性がある(推奨度2)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
柘植雅貴 : 特に申告事項無し[2021年]
茶山一彰 : 報酬額(ギリアド・サイエンシズ(株)),講演料(ギリアド・サイエンシズ(株))[2021年]
監修:金子周一 : 研究費・助成金など(バイエル薬品株式会社,株式会社キュービクス,アボットジャパン合同会社,日東電工株式会社,株式会社スギ薬局,株式会社サイトパスファインダー),奨学(奨励)寄付など(小野薬品工業株式会社,エーザイ株式会社,株式会社ツムラ,アッヴィ合同会社,大日本住友製薬株式会社,ゼリア新薬工業株式会社,塩野義製薬株式会社,大塚製薬株式会社,アステラス製薬株式会社,田辺三菱製薬株式会社,マイランEPD合同会社,EAファーマ株式会社,大鵬薬品工業株式会社,中外製薬株式会社,協和キリン株式会社,持田製薬株式会社,日本ケミファ株式会社,LifeScan Japan株式会社)[2021年]

改訂のポイント:
  1. B型肝炎治療ガイドラインの改訂に伴う変更を行った。
  1. 免疫抑制・化学療法により発症する B 型肝炎対策ガイドラインについて追記した。

病態・疫学・診察

治療のまとめ  
  1. 日本肝臓学会のB型肝炎治療ガイドライン(第3.4版)では、抗ウイルス療法の短期目標と長期目標が示されている[1]
  1. 抗ウイルス療法の長期目標は、HBs抗原消失である[1]
  1. 抗ウイルス療法の短期目標は、HBe抗原、HBV DNA量を陰性化し、ALTを正常化することで、肝炎の鎮静化を持続し、肝癌を予防することにある[1]
  1. 治療には、抗ウイルス療法と肝庇護療法があるが、現在は抗ウイルス療法が中心となっている。
  1. 抗ウイルス療法薬としては、主に核酸アナログ製剤とインターフェロン製剤がある。
  1. 核酸アナログ治療は、長期間の継続が必要であり、治療を中止することで、肝炎が増悪する可能性がある。
  1. 長期間の核酸アナログ治療により、薬剤に耐性を示すウイルスが増殖することがある。
 
抗ウイルス治療の基本方針

*1 HBe抗原セロコンバージョン率やHBV DNA陰性化率が必ずしも高くはないこと、個々の症例における治療前の効果予測が困難であること、予想される副作用などを十分に説明すること。
*2 挙児希望がないことを確認した上で、長期継続投与が必要なこと、耐性変異のリスクがあることを十分に説明すること。核酸アナログ製剤の選択においては、それぞれの薬剤の特性を参考にする。
*3 ALT正常化、HBV DNA量低下(HBs抗原量低下)、さらにHBe抗原陽性例ではHBe抗原陰性化を参考とし、治療終了後24~48週時点で判定する。
*4 ETV中止後再燃時の再治療基準:HBV DNA 100,000 IU/mL(5.0 LogIU/mL)以上、またはALT 80 U/L以上。

 
  1. 核酸アナログの第1選択は、エンテカビル(バラクルード)またはテノホビル(TDF:テノゼット、TAF:ベムリディ)である。エンテカビル・テノホビルは、薬剤耐性ウイルスの出現率が低い。
  1. エンテカビルを長期投与した際の薬剤耐性出現率は、5年間の投与で約1.2%(わが国では4年で0.4%)との報告がある[2][3]
  1. 国外からのTDF(テノゼット)長期投与例を対象とした臨床研究では5年間で薬剤耐性出現はないと報告されているが[4]、近年、TDF耐性が疑われる症例が国内外から報告されている。
  1. TAF(ベムリディ)は、2016年12月に承認された薬剤であるため、長期投与した際の薬剤耐性出現率は明らかとなっていない。
  1. インターフェロン治療により、HBsのセロコンバージョン率が向上する可能性がある。
 
  1. 他の核酸アナログ製剤(ラミブジン、アデホビル)に比して、エンテカビル(バラクルード)やテノホビル(テノゼット、ベムリディ)の長期投与による薬剤耐性獲得率は非常に低い。なお、TAF(ベムリディ)については、承認間もないため、長期投与の治療成績がなく、薬剤耐性獲得率も現在のところ不明である(推奨度1)。
  1. まとめ:核酸アナログ初回投与例において、ラミブジン耐性変異の出現率は、1年で11%、2年で29%、5年で60%以上と報告されている[5]。一方、エンテカビルを投与した症例における耐性出現率は、5年で1.2%程度であり、また、テノホビルを5年間投与した症例における耐性出現は認められていないことから、明らかに耐性獲得率は低いといえる[3]。そのため、現在では、エンテカビルおよびテノホビルが核酸アナログ治療の第1選択として使用され、薬剤耐性出現例や効果不良例に対して、エンテカビルとテノホビルの併用療法を行う。
  1. 結論:薬剤耐性の出現率が低率であること、良好な抗ウイルス効果を示すことから、現在のガイドラインでも示されているように、核酸アナログ治療の第1選択はエンテカビルとテノホビルである。
  1. 追記:現在、ラミブジンを単独投与されている症例においては、ガイドラインにより、治療中のHBV DNA量に応じて、治療効果良好例ではエンテカビルやテノホビルへの切り替え、治療効果不良例ではテノホビルへの切り替えもしくはエンテカビルとテノホビルの併用療法への変更が推奨されている。
 
治療効果による核酸アナログの選択(日本肝臓学会 B型肝炎治療ガイドライン第3.4版)

*1 国内・海外臨床試験が施行されていない治療法は( )で括った。
*2 核酸アナログ投与中の治療目標はHBV DNA陰性化である(治療開始後12か月以降に判定)。治療開始後12か月時点でHBV DNAが陰性化していない場合には、HBV DNAが減少傾向であれば、ETV、TDF、TAFについては治療を継続するが、減少傾向がなければ治療薬を変更する。特にHBV DNA量2,000 IU/mL(3.3 LogIU/mL)以上では治療薬を変更すべきである。治療中にHBV DNAが1.0 LogIU/mL以上上昇するブレイクスルーでは迅速に治療薬を変更する。いずれの場合も服薬アドヒアランスが保たれていることを確認する必要がある。
*3 耐性変異出現の可能性を考慮し、ETV(レベル1b、グレードA)あるいはTAF(レベル6、グレードA)への切り替えが推奨される。
*4 長期的な副作用出現の可能性を考慮し、TDFからTAFへ切り替えることも選択肢となる(レベル2a、グレードB)。腎機能障害、低P血症、骨減少症・骨粗鬆症を認める場合は、TAFへの切り替えが推奨される(レベル2a、グレードA)。
*5 長期的な副作用出現の可能性を考慮し、ADV併用やTDF併用からTAF併用へ切り替えることも選択肢となる(レベル 2a、グレードB)。腎機能障害、低P血症、骨減少症・骨粗鬆症を認める場合は、TAF併用への切り替えが推奨される(レベル2a、グレードA)。
*6 TAF併用の臨床試験は行われていない(レベル6、グレードC1)。
*7 国内臨床試験は行われていないが、海外でのETV耐性例に対する臨床試験においてTDF単剤とETV+TDF併用の効果が同等であることが示されている(レベル1b、グレードA)。
*8 TDFあるいはTAF治療効果不良例に対するETV単剤、ETV+TDFないしETV+TAF併用の臨床試験は行われていない(レベル6、グレードC1)。
*9 ADVとTDFには交叉耐性があり、ETV耐性例に対するTDFを含むレジメンの海外臨床試験において、ADV既治療例では抗ウイルス効果が減弱したことから、TDF単剤ではなくTDF併用を推奨する(レベル4、グレードB)。
*10 TAFの効果はTDFと同等であることが示されているため、TAFについても単剤ではなく併用を推奨する(レベル6、グレードB)。
*11 LAM+TDF併用の治療効果不良例に対するETV+TDF併用やETV+TAF併用の臨床試験は行われていない(レベル6、グレードC1)。
*12 ETV+TDF併用で治療効果不良である場合、現時点で明らかに有効な代替治療法はない。

 
  1. 核酸アナログ製剤の登場や肝移植技術の向上により、B型急性肝炎からの肝不全症例の救命率は向上した(推奨度2)。
  1. まとめ:B型急性肝炎は、無症状であったり、無治療で自然寛解したりするケースが多く、成人感染の場合、95%以上の症例は完全寛解に至る。しかし、1%前後の症例では、劇症化に至る症例が存在する。重症化や劇症化が認められた場合、核酸アナログ製剤の投与や免疫抑制療法・肝移植などが行われることになるが、核酸アナログ製剤の登場・肝移植の成績向上により、救命率は向上しており、少数例の検討ではあるが、本報告によると、B型急性肝炎により急性肝不全となった症例の救命率は78%と向上していた[6]
  1. 結論:B型急性肝炎の重症化または劇症化例に対して、積極的な核酸アナログ投与や肝移植が行われるようになり、救命率が劇的に向上した。
 
急性肝不全の病因および転帰:ある医療機関で治療を受けた50例の後向きの分析

出典

img1:  Etiology and outcome of acute liver failure: retrospective analysis of 50 patients treated at a single center.
 
 J Gastroenterol Hepatol. 2008 Aug;23(8 P・・・

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文献 

著者: Daniel J Tenney, Ronald E Rose, Carl J Baldick, Kevin A Pokornowski, Betsy J Eggers, Jie Fang, Michael J Wichroski, Dong Xu, Joanna Yang, Richard B Wilber, Richard J Colonno
雑誌名: Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.
Abstract/Text UNLABELLED: Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V +/- L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (> or = 300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (> or = 1 log(10) rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved < 300 copies/mL HBV DNA subsequently developed ETVr.
CONCLUSION: Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance.

PMID 19280622  Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22・・・
著者: Atsushi Ono, Fumitaka Suzuki, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Masahiro Kobayashi, Yoshiyuki Suzuki, Satoshi Saitou, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Sachiyo Watahiki, Rie Mineta, Hiromitsu Kumada
雑誌名: J Hepatol. 2012 Sep;57(3):508-14. doi: 10.1016/j.jhep.2012.04.037. Epub 2012 May 30.
Abstract/Text BACKGROUND & AIMS: We determined the antiviral potency and viral resistance rate after 4 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection.
METHODS: The cumulative rates of undetectable hepatitis B virus DNA (HBV DNA;<2.6 log(10) copies/ml), hepatitis B e antigen (HBeAg) seronegativity, seroconversion, alanine aminotransferase (ALT) normalization, and entecavir signature mutations were calculated in 474 nucleos(t)ide-naïve CHB patients (HBeAg-positive: 47%) on continuous entecavir treatment for 4 years.
RESULTS: Median age was 47 years and follow-up period was 2.4 years, with 403, 281, 165, and 73 patients followed-up for at least 1, 2, 3, and 4 years, respectively. Incremental increases were observed in the rates of undetectable HBV DNA, HBeAg seroclearance and seroconversion, and ALT normalization, reaching 96%, 42%, 38% and 93%, respectively, by the fourth year. In all, 100% and 93% of patients negative and positive for HBeAg, respectively, had undetectable HBV DNA at year 4. Of 165 patients, HBV DNA was detectable in nine patients after 3 years. Multivariate analysis identified HBV DNA level (≤7.6 log(10) copies/ml, OR=15.8; 95% CI=43.1-79.9, P=0.001) as an independent predictor of undetectable HBV DNA at year 3. Five patients experienced virological breakthrough including two (0.4%) who developed entecavir-resistance mutations.
CONCLUSIONS: Continuous treatment of nucleos(t)ide-naïve CHB patients with entecavir over 4 years was associated with 96% chance of undetectable HBV DNA and only 0.4% chance of emerging entecavir-resistant mutations.

Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID 22659518  J Hepatol. 2012 Sep;57(3):508-14. doi: 10.1016/j.jhep.2・・・
著者: Patrick Marcellin, Edward Gane, Maria Buti, Nezam Afdhal, William Sievert, Ira M Jacobson, Mary Kay Washington, George Germanidis, John F Flaherty, Raul Aguilar Schall, Jeffrey D Bornstein, Kathryn M Kitrinos, G Mani Subramanian, John G McHutchison, E Jenny Heathcote
雑誌名: Lancet. 2013 Feb 9;381(9865):468-75. doi: 10.1016/S0140-6736(12)61425-1. Epub 2012 Dec 10.
Abstract/Text BACKGROUND: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection.
METHODS: After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system).
FINDINGS: Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug.
INTERPRETATION: In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis.
FUNDING: Gilead Sciences.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23234725  Lancet. 2013 Feb 9;381(9865):468-75. doi: 10.1016/S0140・・・
著者: Mariko Kobayashi, Fumitaka Suzuki, Norio Akuta, Hiromi Yatsuji, Tetsuya Hosaka, Hitomi Sezaki, Masahiro Kobayashi, Yusuke Kawamura, Yoshiyuki Suzuki, Yasuji Arase, Kenji Ikeda, Rie Mineta, Satomi Iwasaki, Sachiyo Watahiki, Hiromitsu Kumada
雑誌名: Hepatol Res. 2010 Feb;40(2):125-34. doi: 10.1111/j.1872-034X.2009.00565.x. Epub 2009 Sep 25.
Abstract/Text Aim: Continuous lamivudine treatment is associated with high frequency of drug resistance. We analyzed the incidence of tyrosine-methionine-aspartate-aspartate (YMDD) motif mutant and breakthrough hepatitis (BTH) in hepatitis B virus (HBV) DNA positive patients receiving lamivudine for > 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy. Methods: Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of /= 3 years. Results: The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT
PMID 19788696  Hepatol Res. 2010 Feb;40(2):125-34. doi: 10.1111/j.1872・・・
著者: Akira Hiramatsu, Shoichi Takahashi, Hiroshi Aikata, Takahiro Azakami, Yoshio Katamura, Tomokazu Kawaoka, Kiminori Uka, Keitaro Yamashina, Shintaro Takaki, Hideaki Kodama, Soo Cheol Jeong, Michio Imamura, Yoshiiku Kawakami, Kazuaki Chayama
雑誌名: J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1216-22. doi: 10.1111/j.1440-1746.2008.05402.x. Epub 2008 Jul 10.
Abstract/Text BACKGROUND AND AIM: Acute liver failure (ALF) remains a devastating disease carrying considerable mortality. Since deceased donor liver transplantation is rarely performed in Japan, the artificial liver support system (ALS) and living donor liver transplantation (LDLT) are the main modalities used for treatment of ALF. The aim of this study was to analyze the outcome of ALF patients and to evaluate therapies for ALF according to etiology.
METHODS: Fifty consecutive patients with ALF were treated between January 1990 and December 2006. Prior to 1997, patients received ALS only. After 1997, ALS and/or LDLT were applied. LDLT was performed in 10 patients.
RESULTS: Four of 15 (27%) pre-1997 ALF patients survived, and 16 of 35 (46%) post-1997 ALF patients survived, including eight who underwent LDLT. The causes of ALF were acute hepatitis B virus (HBV) infection in 18%, severe acute exacerbation (SAE) of chronic HBV infection in 18%, autoimmune hepatitis (AIH) in 8%, and cryptogenic hepatitis in 44%. In total, 67% of the patients with ALF caused by acute HBV infection and AIH were cured without LDLT; only 11% of patients with ALF caused by SAE of HBV and 24% of cryptogenic hepatitis were successfully treated without LDLT. Notably, 80% of patients with cryptogenic hepatitis who underwent LDLT survived.
CONCLUSION: Since 1997, the survival rate of ALF patients has increased, mainly due to the introduction of LDLT. Liver transplantation should be performed especially in patients with ALF caused by SAE of HBV and cryptogenic hepatitis.

PMID 18637059  J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1216-22. d・・・
著者: Yasuhito Tanaka, Izumi Hasegawa, Takanobu Kato, Etsuro Orito, Noboru Hirashima, Subrat K Acharya, Robert G Gish, Anna Kramvis, Michael C Kew, Namiko Yoshihara, Santosh Man Shrestha, Mobin Khan, Yuzo Miyakawa, Masashi Mizokami
雑誌名: Hepatology. 2004 Sep;40(3):747-55. doi: 10.1002/hep.20365.
Abstract/Text There are two subtypes of hepatitis B virus genotype A (HBV/A) and they are provisionally designated Aa ("a" standing for Africa/Asia) and Ae ("e" for Europe). In a case-control study, 78 HBV/Aa, 78HBV/Ae, and 78HBV/D carriers from several countries were compared. The prevalence of HBe antigen (HBeAg) in serum was significantly lower in carriers of HBV/Aa than in carriers of HBV/Ae (31% vs. 49%; P = .033), with a difference more obvious in the carriers aged 30 years or younger (34% vs. 67%; P = .029). HBV DNA levels in the carriers of HBV/Aa (median, 3.46 log copies/mL; 95% CI, 2.93-3.95) were significantly lower than those of carriers of HBV/Ae (6.09 log copies/mL; 95% CI, 4.24-7.64) or of carriers of HBV/D (5.48 log copies/mL; 95% CI, 4.06-7.02), regardless of the HBeAg status (P < .001). The most specific and frequent substitutions in 54 HBV/Aa isolates were double substitutions for T1809 (100%) and T1812 (96%) immediately upstream of the precore initiation codon, which would interfere with the translation of HBeAg in HBV/Aa infections. They were not detected in 57 HBV/Ae or 61 HBV/D isolates examined. The double mutation in the core promoter (T1762/A1764) was more frequent in both HBV/Aa (50%) and HBV/Ae (44%) than in HBV/D isolates (25%; P < .01), whereas the precore mutation (A1896) occurred in HBV/D isolates only (48%; P < .0001). In conclusion, the clearance of HBeAg from serum may occur by different mechanisms in HBV/Aa, HBV/Ae, and HBV/D infections, which may influence clinical manifestations in the Western countries where both genotypes A and D are prevalent.

Copyright 2004 American Association for the Study of Liver Diseases
PMID 15349915  Hepatology. 2004 Sep;40(3):747-55. doi: 10.1002/hep.203・・・
著者: Emmet B Keeffe, Douglas T Dieterich, Steven-Huy B Han, Ira M Jacobson, Paul Martin, Eugene R Schiff, Hillel Tobias, Teresa L Wright
雑誌名: Clin Gastroenterol Hepatol. 2006 Aug;4(8):936-62. doi: 10.1016/j.cgh.2006.05.016. Epub 2006 Jul 14.
Abstract/Text Chronic hepatitis B (CHB) is an important public health problem worldwide and in the United States, with approximately 25% of patients infected as neonates dying prematurely from cirrhosis or liver cancer. A treatment algorithm for CHB previously developed and published by a panel of United States hepatologists was revised based on new developments in the understanding of CHB, the availability of more sensitive molecular diagnostic testing, the addition of new treatments, and better understanding of the advantages and disadvantages of approved therapies. This updated algorithm is based on available evidence using a systematic review of the scientific literature. Where data are lacking, the panel relied on clinical experience and consensus expert opinion. Serum HBV DNA can be detected at levels as low as 10 IU/mL using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest levels possible. The threshold level of HBV DNA for determination of candidacy for therapy is 20,000 IU/mL or more for patients with hepatitis B e antigen-positive CHB. A lower serum HBV DNA threshold of 2000 IU/mL or more is recommended for patients with hepatitis B e antigen-negative CHB, and 200 IU/mL or more for those with decompensated cirrhosis. Interferon alfa-2b, lamivudine, adefovir, entecavir, and peginterferon alfa-2a all are approved as initial therapy for CHB and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost.

PMID 16844425  Clin Gastroenterol Hepatol. 2006 Aug;4(8):936-62. doi: ・・・
著者: J M Lopez-Alcorocho, J Bartolome, T Cotonat, V Carreño
雑誌名: J Viral Hepat. 1997;4 Suppl 1:27-32.
Abstract/Text We compared the response and the relapse rates of HBeAb-positive patients treated with interferon-alpha for 6 or 12 months. Thirty-eight HBeAb-positive patients which chronic hepatitis B were randomly allocated into two groups: Group I (19 patients receiving 10 MU of recombinant interferon-alpha 2b three times a week for 2 months, followed by 5 MU three times a week for 2 months and then 3 MU three times a week for 2 months); Group II (19 patients receiving 10 MU of recombinant interferon-alpha 2b three times a week for 2 months, followed by 5 MU three times a week for 2 months and then 3 MU three times a week for 8 months). At the end of treatment, alanine aminotransferase normalization was higher but not more significant in Group I than in II (53% vs 26%), while hepatitis B virus DNA clearance was similar in both groups (21% in Group I vs 26% in Group II). However, at 12 months of follow-up, biochemical relapses occurred only in Group I (60% vs 0% in Groups I and II, respectively). Five complete responders cleared hepatitis B surface antigen at that time. In conclusion, prolonged treatment of HBeAb patients is efficient in reducing the biochemical relapse.

PMID 9097275  J Viral Hepat. 1997;4 Suppl 1:27-32.
著者: H L Janssen, G Gerken, V Carreño, P Marcellin, N V Naoumov, A Craxi, H Ring-Larsen, G Kitis, J van Hattum, R A de Vries, P P Michielsen, F J ten Kate, W C Hop, R A Heijtink, P Honkoop, S W Schalm
雑誌名: Hepatology. 1999 Jul;30(1):238-43. doi: 10.1002/hep.510300113.
Abstract/Text Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

PMID 10385662  Hepatology. 1999 Jul;30(1):238-43. doi: 10.1002/hep.510・・・
著者: Young-Hwa Chung, Byung-Cheol Song, Geun Chan Lee, Jung Woo Shin, Soo Hyung Ryu, Sung Ae Jung, Kwon Yoo, Han Chu Lee, Yung Sang Lee, Dong Jin Suh
雑誌名: Eur J Gastroenterol Hepatol. 2003 May;15(5):489-93. doi: 10.1097/01.meg.0000059120.41030.52.
Abstract/Text OBJECTIVE: In patients with chronic hepatitis B, viral relapse following interferon (IFN) therapy may be the result of a treatment duration that is too short to prevent hepatitis B virus (HBV) from replicating later. To reduce viral relapse in patients with chronic hepatitis B who responded to IFN, we individualized the duration of therapy according to serum HBV-DNA levels.
METHOD: Treatment duration was prolonged to maintain negative serum HBV-DNA levels for the next 6 months in 30 patients who became HBV-DNA-negative following IFN therapy (group A). Another 35 patients were treated for only 6 months (group B). All patients had HBV-DNA as well as hepatitis B surface antigen (HBsAg) in their sera for more than 6 months and were proven histologically to have chronic hepatitis. Interferon alfa (IFN-alpha) was administered subcutaneously at a dose of 5 MU/m2 three times a week.
RESULTS: There were no differences in age, gender, hepatitis B e antigen (HBeAg) positivity, serum alanine aminotransferase (ALT) levels, or serum HBV-DNA levels between the two groups. The mean duration of IFN therapy in group A was 7.2 months. At the end of treatment, serum HBV-DNA was negative in 16 patients in group A and in 18 patients in group B. The loss of serum HBV-DNA was maintained to the end of follow-up in 13 patients in group A but in only eight patients in group B. Similarly, serum ALT levels were normal in 14 patients in group A but in only nine patients in group B at the end of follow-up.
CONCLUSION: Individualization of the duration of treatment to maintain serum HBV-DNA negativity for at least 6 months may reduce the viral relapse rate following IFN therapy.

PMID 12702905  Eur J Gastroenterol Hepatol. 2003 May;15(5):489-93. doi・・・
著者: W G E Cooksley, T Piratvisuth, S-D Lee, V Mahachai, Y-C Chao, T Tanwandee, A Chutaputti, W Yu Chang, F E Zahm, N Pluck
雑誌名: J Viral Hepat. 2003 Jul;10(4):298-305. doi: 10.1046/j.1365-2893.2003.00450.x.
Abstract/Text Current therapies for chronic hepatitis B (CHB) have a number of limitations, and better treatment options are needed. Peginterferon alpha-2a (40 kDa) is superior to conventional interferon alpha-2a in the treatment of chronic hepatitis C. This is the first report on peginterferon alpha-2a (40 kDa) in the treatment of CHB. In this phase II study, 194 patients with CHB not previously treated with conventional interferon-alpha were randomized to receive weekly subcutaneous doses of peginterferon alpha-2a (40 kDa) 90, 180 or 270 microg, or conventional interferon alpha-2a 4.5 MIU three times weekly. Twenty-four weeks of therapy were followed by 24 weeks of treatment-free follow-up. All subjects were assessed for loss of hepatitis B e antigen (HBeAg), presence of hepatitis B antibody (anti-HBe), suppression of hepatitis B virus (HBV) DNA, and normalization of serum alanine transaminase (ALT) after follow-up. At the end of follow-up, HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon alpha-2a (40 kDa) 90, 180 and 270 microg, respectively, compared with 25% of patients on conventional interferon alpha-2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon alpha-2a (40 kDa) doses combined was twice that achieved with conventional interferon alpha-2a (24%vs 12%; P = 0.036). All treatment groups were similar with respect to frequency and severity of adverse events. These results indicate that peginterferon alpha-2a (40 kDa) is superior in efficacy to conventional interferon alpha-2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT.

PMID 12823597  J Viral Hepat. 2003 Jul;10(4):298-305. doi: 10.1046/j.1・・・
著者: Moira A McMahon, Benjamin L Jilek, Timothy P Brennan, Lin Shen, Yan Zhou, Megan Wind-Rotolo, Sifei Xing, Shridhar Bhat, Braden Hale, Robert Hegarty, Curtis R Chong, Jun O Liu, Robert F Siliciano, Chloe L Thio
雑誌名: N Engl J Med. 2007 Jun 21;356(25):2614-21. doi: 10.1056/NEJMoa067710.
Abstract/Text Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.

Copyright 2007 Massachusetts Medical Society.
PMID 17582071  N Engl J Med. 2007 Jun 21;356(25):2614-21. doi: 10.1056・・・
著者: E J Fisher, K Chaloner, D L Cohn, L B Grant, B Alston, C L Brosgart, B Schmetter, W M El-Sadr, J Sampson, Terry Beirn Community Programs for Clinical Research on AIDS
雑誌名: AIDS. 2001 Sep 7;15(13):1695-700.
Abstract/Text OBJECTIVE: Efficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease.
DESIGN: Randomized, double-blind, placebo-controlled multicenter trial.
SETTING: Fifteen clinical trial units providing HIV primary care.
PARTICIPANTS: Adults with CD4 cell count < or = 100 x 10(6)/l, or 101-200 x 10(6)/l with prior nadir < or = 50 x 10(6)/l.
INTERVENTIONS: Oral adefovir or placebo 120 mg once daily.
MAIN OUTCOME MEASURES: Survival, cytomegalovirus (CMV) disease, plasma HIV-RNA, CD4 cell count, grade 4 drug toxicity, permanent drug discontinuation due to toxicity.
RESULTS: Among the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (P = 0.88), and four and eight experienced CMV disease (P = 0.25). Mean change in log(10) plasma HIV-RNA in the adefovir and placebo groups, respectively, was 0.09 and -0.03 copies/ml at 6 months (P = 0.22) and 0.06 and -0.02 at 12 months (P = 0.87). Changes in CD4 cell counts were not different between groups. At 12 months the cumulative percent with proximal renal tubular dysfunction (PRTD) was 17% in the adefovir group and 0.4% in the placebo group (P < 0.0001, log rank test). Median time to resolution of PRTD was 15 weeks among patients assigned adefovir, and 16% of patients did not resolve completely 41 weeks after onset. More drug discontinuations occurred in the adefovir group than in the placebo group.
CONCLUSIONS: No virologic or immunologic benefit was observed when adefovir was added to background antiretroviral therapy in advanced HIV disease, and adefovir was associated with considerable nephrotoxicity. This study does not support the use of adefovir for treatment of advanced HIV disease in pretreated patients.

PMID 11546945  AIDS. 2001 Sep 7;15(13):1695-700.
著者: Fukiko Mitsui, Masataka Tsuge, Takashi Kimura, Shosuke Kitamura, Hiromi Abe, Hiromi Saneto, Tomokazu Kawaoka, Daiki Miki, Tsuyoshi Hatakeyama, Nobuhiko Hiraga, Michio Imamura, Yoshiiku Kawakami, Hiroshi Aikata, Shoichi Takahashi, C Nelson Hayes, Harue Igarashi, Kentaro Morimoto, Masao Shimizu, Kazuaki Chayama
雑誌名: Antimicrob Agents Chemother. 2010 Aug;54(8):3205-11. doi: 10.1128/AAC.01372-09. Epub 2010 May 24.
Abstract/Text Lamivudine (LMV)-adefovir pivoxil (ADV) combination therapy suppresses the replication of LMV-resistant hepatitis B virus (HBV), although its efficacy in suppressing HBV varies among patients. This study analyzed the clinical, virological, and pharmaceutical factors that influence the effect of the combination therapy. Patients negative for hepatitis B virus e antigen (HBeAg) and with low HBV DNA titers immediately prior to the combination therapy effectively cleared serum HBV DNA (P=0.0348 and P=0.0310, respectively). The maximum concentration of ADV in serum (ADV Cmax) was higher in patients who showed HBV DNA clearance (P=0.0392), and the cumulative clearance rates of HBV DNA were significantly higher in patients with ADV Cmax equal to or greater than 24 ng/ml (P=0.0284). HBeAg negativity and lower HBV DNA at the start of the combination therapy and higher ADV Cmax were found to be independent factors for serum HBV DNA clearance. Serum creatinine increased significantly during the combination therapy, and the ADV Cmax was higher in patients with low creatinine clearance rates. In conclusion, higher serum concentrations of ADV are associated with a good response to therapy based on clearance of HBV DNA in serum. However, care should be taken to prevent worsening of renal function due to high ADV serum concentrations.

PMID 20498322  Antimicrob Agents Chemother. 2010 Aug;54(8):3205-11. do・・・
著者: Patrick Marcellin, Ting-Tsung Chang, Seng G Lee Lim, William Sievert, Myron Tong, Sarah Arterburn, Katyna Borroto-Esoda, David Frederick, Franck Rousseau
雑誌名: Hepatology. 2008 Sep;48(3):750-8. doi: 10.1002/hep.22414.
Abstract/Text UNLABELLED: Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log(10) copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 x upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log(10) copies/mL and -50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV.
CONCLUSION: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement.

PMID 18752330  Hepatology. 2008 Sep;48(3):750-8. doi: 10.1002/hep.2241・・・
著者: A Tamori, M Enomoto, S Kobayashi, S Iwai, H Morikawa, H Sakaguchi, D Habu, S Shiomi, Y Imanishi, N Kawada
雑誌名: J Viral Hepat. 2010 Feb 1;17(2):123-9. doi: 10.1111/j.1365-2893.2009.01160.x. Epub 2009 Aug 5.
Abstract/Text Combination therapy with adefovir dipivoxil (ADV) and lamivudine (LAM) is recommended for patients infected with LAM-refractory hepatitis B virus (HBV). However, the effects of such therapy on renal function and serum phosphorus levels have not been fully evaluated. Combination therapy with ADV and LAM was given to 37 patients infected with LAM-refractory HBV, including 17 with hepatic cirrhosis. Serum HBV DNA levels decreased to below 2.6 log(10) copies/mL in 23 (62%) of 37 patients at 12 months, 25 (78%) of 32 patients at 24 months, and 16 (84%) of 19 patients at 36 months. Except for one cirrhotic patient, serum alanine aminotransferase levels were below 50 IU/L in all patients during combination therapy. Serum creatinine levels increased in 14 (38%) of 37 patients, and serum phosphate levels decreased to below 2.5 mg/mL in 6 (16%) of 37 patients during combination therapy. Patients who received combination therapy for 36 months or longer had a significantly incidence of elevated serum creatinine levels. Fanconi syndrome occurred in a 57-year-old woman with cirrhosis after ADV was added to LAM. Combination therapy with ADV and LAM can maintain biochemical remission in patients with LAM-refractory HBV. However, the dosing interval of ADV should be adjusted according to renal function and serum phosphate levels in patients receiving long-term treatment.

PMID 19674281  J Viral Hepat. 2010 Feb 1;17(2):123-9. doi: 10.1111/j.1・・・
著者: Mio Tanaka, Fumitaka Suzuki, Yuya Seko, Tasuku Hara, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Masahiro Kobayashi, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
雑誌名: J Gastroenterol. 2014 Mar;49(3):470-80. doi: 10.1007/s00535-013-0779-0. Epub 2013 Mar 26.
Abstract/Text BACKGROUND: Renal dysfunction and Fanconi's syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM).
METHODS: The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months.
RESULT: During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR < 50 ml/min/1.73 m(2)), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi's syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline.
CONCLUSION: Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.

PMID 23525978  J Gastroenterol. 2014 Mar;49(3):470-80. doi: 10.1007/s0・・・
著者: Melissa D Murphy, Mary O'Hearn, Sunwen Chou
雑誌名: Clin Infect Dis. 2003 Apr 15;36(8):1082-5. doi: 10.1086/368313. Epub 2003 Apr 3.
Abstract/Text We describe a 49-year-old man with human immunodeficiency virus infection and stable chronic renal insufficiency who developed acute oliguric renal failure and severe lactic acidosis and who died several weeks after tenofovir was added to an antiretroviral regimen that included didanosine. Although the role of tenofovir in precipitating acute renal failure is unclear, progressive accumulation of the drug and pharmacologic interaction that caused increased levels of didanosine were the likely antecedents of increased mitochondrial toxicity that led to lactic acidosis.

PMID 12684925  Clin Infect Dis. 2003 Apr 15;36(8):1082-5. doi: 10.1086・・・
著者: Hélène Peyrière, Jacques Reynes, Isabelle Rouanet, Nathalie Daniel, Corinne Merle de Boever, Jean-Marc Mauboussin, Hélène Leray, Laurence Moachon, Denis Vincent, Dominique Salmon-Céron
雑誌名: J Acquir Immune Defic Syndr. 2004 Mar 1;35(3):269-73.
Abstract/Text We describe 7 cases of renal tubular injury in HIV-infected patients receiving an antiretroviral regimen containing tenofovir. Our patients (5 women and 2 men) developed renal tubular dysfunction, with hypophosphatemia, normoglycemic glycosuria, proteinuria, and decrease of creatinine clearance. The first biologic signs of renal toxicity were observed after duration of tenofovir treatment from 5 weeks to 16 months, and they resolved less than 4 months after discontinuation of tenofovir. Six patients had a low body weight (<60 kg). Five patients received low doses of ritonavir, and 1 received didanosine. In 5 patients, the signs resolved with the discontinuation of only the tenofovir. A renal biopsy performed in 1 patient was consistent with tubulointerstitial injury. Proximal tubulopathy appears to be a rare adverse effect of long-term tenofovir therapy. In patients with low weight or mild preexisting renal impairment, regular monitoring of tubulopathy markers could lead to early detection of this dysfunction.

PMID 15076241  J Acquir Immune Defic Syndr. 2004 Mar 1;35(3):269-73.
著者: Alexandre Karras, Matthieu Lafaurie, André Furco, Anne Bourgarit, Dominique Droz, Daniel Sereni, Christophe Legendre, Frank Martinez, Jean-Michel Molina
雑誌名: Clin Infect Dis. 2003 Apr 15;36(8):1070-3. doi: 10.1086/368314. Epub 2003 Apr 4.
Abstract/Text We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

PMID 12684922  Clin Infect Dis. 2003 Apr 15;36(8):1070-3. doi: 10.1086・・・
著者: Yun-Fan Liaw
雑誌名: Hepatology. 2011 Jun;53(6):2121-9. doi: 10.1002/hep.24364.
Abstract/Text This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice.

Copyright © 2011 American Association for the Study of Liver Diseases.
PMID 21503943  Hepatology. 2011 Jun;53(6):2121-9. doi: 10.1002/hep.243・・・
著者: Henry Lik-Yuen Chan, Alex Thompson, Michelle Martinot-Peignoux, Teerha Piratvisuth, Markus Cornberg, Maurizia Rossana Brunetto, Hans L Tillmann, Jia-Horng Kao, Ji-Dong Jia, Heiner Wedemeyer, Stephen Locarnini, Harry L A Janssen, Patrick Marcellin
雑誌名: J Hepatol. 2011 Nov;55(5):1121-31. doi: 10.1016/j.jhep.2011.06.006. Epub 2011 Jun 28.
Abstract/Text Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000IU/ml), HBsAg <1000IU/ml in genotype D HBV infection and HBsAg <100IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID 21718667  J Hepatol. 2011 Nov;55(5):1121-31. doi: 10.1016/j.jhep.・・・
著者: Henry L-Y Chan, Grace L-H Wong, Angel M-L Chim, Hoi-Yun Chan, Shirley H-T Chu, Vincent W-S Wong
雑誌名: Antivir Ther. 2011;16(8):1249-57. doi: 10.3851/IMP1921.
Abstract/Text BACKGROUND: The timing of antiviral therapy cessation in hepatitis B e antigen (HBeAg)-negative patients is controversial. Here, we aimed to investigate the role of HBV DNA and hepatitis B surface antigen (HBsAg) monitoring to predict off-treatment sustained response.
METHODS: A total of 53 HBeAg-negative chronic hepatitis B patients who received lamivudine for 34 ±23 (range 12-76) months and had lamivudine stopped for 47 ±35 months were studied. Primary outcome was sustained response, defined as HBV DNA≤200 IU/ml, at 12 months post-treatment (SR-12).
RESULTS: A total of 9 (17%) patients achieved SR-12. HBV DNA at baseline, month 6 and end of treatment had no association with SR-12. HBsAg levels tended to decrease more significantly during treatment among SR-12 responders. At the end of treatment, both HBsAg ≤2 log IU/ml and reduction by >1 log from baseline had sensitivity, specificity, positive and negative predictive values for SR-12 of 78%, 96%, 78% and 96%, respectively. All 5 patients with HBsAg≤2 log IU/ml and reduction >1 log at the end of treatment achieved SR-12 and all 40 patients with HBsAg>2 log IU/ml and reduction ≤1 log did not have SR-12. The cumulative probability of sustained response and HBsAg clearance at 5 years among patients with HBsAg≤2 log IU/ml were 88% and 72%, respectively, that among patients with HBsAg reduction >1 log were 74% and 61%, respectively.
CONCLUSIONS: Monitoring of HBsAg level can guide the timing of stopping lamivudine in HBeAg-negative chronic hepatitis B.

PMID 22155906  Antivir Ther. 2011;16(8):1249-57. doi: 10.3851/IMP1921.・・・
著者: Necati Ormeci, Füsun Bölükbaş, Esra Erden, Sahin Coban, Fuat Ekiz, Hakan Erdem, Murat Palabıyıkoğlu, Ali Reşit Beyler, Ismail Balık, Cengiz Bölükbaş, Yaşar Nazlıgül, Seyfettin Köklü
雑誌名: Hepatogastroenterology. 2011 Sep-Oct;58(110-111):1648-53. doi: 10.5754/hge10126.
Abstract/Text BACKGROUND/AIMS: The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) alfa-2b for short (one year) and long (two years) terms of treatment for chronic hepatitis D.
METHODOLOGY: Eighteen patients with chronic hepatitis D were administered PEG-IFN alfa-2b 1.5μg/kg twice weekly for 1 month, after which they were randomly assigned (2:1) to receive PEG-IFN alfa-2b 1.5μg/kg/wk for an additional 23 months (n=11; group 1) or 11 months (n=7; group 2). All patients were followed-up for 6 months after completing therapy.
RESULTS: In group 1, there was no significant difference between HDV-RNA and ALT levels at follow-up compared with baseline (p=0.219 and p=0.624, respectively). However, in group 2, HDVRNA levels, but not ALT levels, were significantly lower at the end of follow-up (EOF) than at baseline (p=0.016 and p=0.237, respectively). Three patients, all in group 2, had undetectable hepatitis B surface antigen (HBsAg) at the end of followup (EOF). However, there was no patient who had undetectable HBsAg in group I (p=0.043). There were statistical differences for all 18 patients in terms of baseline levels of HDV-RNA compared to end of treatment (EOT) (p=0.021) and EOF (p=0.003).
CONCLUSIONS: Extending therapy from 12 to 24 months conferred no additional advantage in terms of HDV-RNA suppression and ALT normalisation.

PMID 22086695  Hepatogastroenterology. 2011 Sep-Oct;58(110-111):1648-5・・・
著者: Milan J Sonneveld, Harry L A Janssen
雑誌名: Liver Int. 2011 Jan;31 Suppl 1:78-84. doi: 10.1111/j.1478-3231.2010.02384.x.
Abstract/Text Pegylated interferon-α (PEG-IFN) is still an important treatment option for both HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) patients even with the availability of potent nucleos(t)ide analogues (NUCs) with a low risk of resistance. The major advantages of PEG-IFN-based treatment include the limited duration of treatment and the good probability of achieving a sustained off-treatment response. Responders to PEG-IFN have an increased probability of HBsAg loss and survival. However, the limited number of patients who achieve a response and the high costs and side-effects associated with PEG-IFN limit its clinical use. The potent NUCs entecavir and tenofovir are therefore often used as a first-line treatment option. Unfortunately, the off-treatment durability of response to NUCs is generally low, requiring long-term continuous therapy. Recent progress making it possible to select patients with a high probability of achieving a response to PEG-IFN, and to adapt therapy early on in probable non-responders, should help further optimize the utilization of PEG-IFN in CHB.

© 2011 John Wiley & Sons A/S.
PMID 21205142  Liver Int. 2011 Jan;31 Suppl 1:78-84. doi: 10.1111/j.14・・・
著者: Jurriën G P Reijnders, Vincent Rijckborst, Milan J Sonneveld, Sandra M J Scherbeijn, Charles A B Boucher, Bettina E Hansen, Harry L A Janssen
雑誌名: J Hepatol. 2011 Mar;54(3):449-54. doi: 10.1016/j.jhep.2010.07.046. Epub 2010 Nov 5.
Abstract/Text BACKGROUND & AIMS: We aimed to investigate serum hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B virus (HBV) infection during peginterferon (PEG-IFN) and entecavir (ETV) monotherapy.
METHODS: HBsAg was quantified (Abbott ARCHITECT) at baseline and during antiviral therapy (weeks 12, 24, 36, 48) in hepatitis B e antigen (HBeAg-) positive patients treated with ETV (n=33) or PEG-IFN (n=61) and in HBeAg-negative patients treated with ETV (n=37) or PEG-IFN (n=69).
RESULTS: Within the HBeAg-positive population, patients treated with PEG-IFN tended to have a steeper HBsAg decline than ETV-treated patients (mean decline 0.94 versus 0.38 log IU/ml at week 48, p=0.07 for comparison of the slope of HBsAg decline). The HBsAg decline was larger in those patients who became HBeAg negative, irrespective of the treatment regimen. A decline in HBsAg was confined to ETV-treated patients with elevated baseline alanine aminotransferase (ALT) levels, whereas HBsAg decline was not associated with baseline ALT in patients treated with PEG-IFN. Within the HBeAg-negative population, PEG-IFN induced a significant HBsAg decline, while HBsAg did not decrease in ETV-treated patients (0.56 versus -0.10 log IU/ml, p<0.001). Both in HBeAg-positive and HBeAg-negative patients, the decline in serum HBV DNA was larger in patients who received ETV as compared to patients treated with PEG-IFN.
CONCLUSIONS: In HBeAg-positive patients, the decline in serum HBsAg is mainly confined to patients who clear HBeAg, by either PEG-IFN or ETV treatment. In HBeAg-negative patients, PEG-IFN therapy resulted in a significant reduction in HBsAg levels, whereas HBsAg did not decrease in ETV-treated patients.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID 21112655  J Hepatol. 2011 Mar;54(3):449-54. doi: 10.1016/j.jhep.2・・・
著者: Milan J Sonneveld, Vincent Rijckborst, Charles A B Boucher, Bettina E Hansen, Harry L A Janssen
雑誌名: Hepatology. 2010 Oct;52(4):1251-7. doi: 10.1002/hep.23844.
Abstract/Text Serum hepatitis B surface antigen (HBsAg) levels may reflect the immunomodulatory efficacy of pegylated interferon (PEG-IFN). We investigated within a large randomized trial whether quantitative HBsAg levels predict response to PEG-IFN in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Serum HBsAg was measured in samples taken at baseline and weeks 4, 8, 12, 24, 52, and 78 of 221 patients treated with PEG-IFN alfa-2b with or without lamivudine for 52 weeks. HBsAg decline was compared between treatment arms and between responders and nonresponders. Response was defined as HBeAg loss with HBV DNA < 10,000 copies/mL at 26 weeks after treatment (week 78); 43 of 221 (19%) patients achieved a response. One year of PEG-IFN with or without lamivudine resulted in a significant decline in serum HBsAg, which was sustained after treatment (decline 0.9 log IU/mL at week 78, P < 0.001). Patients treated with combination therapy experienced a more pronounced on-treatment decline, but relapsed subsequently. Responders experienced a significantly more pronounced decline in serum HBsAg compared to nonresponders (decline at week 52: 3.3 versus 0.7 log IU/mL, P < 0.001). Patients who achieved no decline at week 12 had a 97% probability of nonresponse through posttreatment follow-up and no chance of HBsAg loss. In a representative subset of 149 patients similar results were found for prediction through long-term (mean 3.0 years) follow-up. CONCLUSION: PEG-IFN induces a significant decline in serum HBsAg in HBeAg-positive patients. Patients who experience no decline from baseline at week 12 have little chance of achieving a sustained response and no chance of HBsAg loss and should be advised to discontinue therapy with PEG-IFN.

PMID 20830787  Hepatology. 2010 Oct;52(4):1251-7. doi: 10.1002/hep.238・・・
著者: Vincent Rijckborst, Bettina E Hansen, Yilmaz Cakaloglu, Peter Ferenci, Fehmi Tabak, Meral Akdogan, Krzysztof Simon, Ulus S Akarca, Robert Flisiak, Elke Verhey, Anneke J Van Vuuren, Charles A B Boucher, Martijn J ter Borg, Harry L A Janssen
雑誌名: Hepatology. 2010 Aug;52(2):454-61. doi: 10.1002/hep.23722.
Abstract/Text Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB.

PMID 20683945  Hepatology. 2010 Aug;52(2):454-61. doi: 10.1002/hep.237・・・
著者: Chien-Jen Chen, Hwai-I Yang, Jun Su, Chin-Lan Jen, San-Lin You, Sheng-Nan Lu, Guan-Tarn Huang, Uchenna H Iloeje, REVEAL-HBV Study Group
雑誌名: JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.
Abstract/Text CONTEXT: Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B.
OBJECTIVE: To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma.
DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992.
MAIN OUTCOME MEASURE: Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems.
RESULTS: There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P<.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk.
CONCLUSION: Elevated serum HBV DNA level (> or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.

PMID 16391218  JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.・・・
著者: Jong Ryul Eun, Heon Ju Lee, Tae Nyeun Kim, Kyeung Soo Lee
雑誌名: J Hepatol. 2010 Jul;53(1):118-25. doi: 10.1016/j.jhep.2010.02.026. Epub 2010 Apr 4.
Abstract/Text BACKGROUND & AIMS: To assess the risk for the development of hepatocellular carcinoma (HCC) according to the underlying liver status and on-treatment viral response during long-term lamivudine therapy in patients with hepatitis B virus-related liver disease.
PATIENTS AND METHODS: Between March 1997 and February 2005, a total of 872 patients were treated with lamivudine for more than one year. Between 1983 and 1998, a total of 699 patients were enrolled as historical controls.
RESULTS: For patients with compensated cirrhosis, HCC occurred in 4.9% (5/103) of cases with sustained viral suppression (persistently <141,500 copies/ml), 11.8% (20/170) in cases with viral breakthrough, and 19.4% (7/36) in cases with a suboptimal response (persistently 141,500 copies/ml): the mean follow-up was 5.1+/-2.7, 5.4+/-2.3, and 3.7+/-1.8 years, respectively. For the control group, HCC developed in 25.0% (37/148) of the cases during a mean follow-up of 6.1+/-4.3 years. Thus, the annual incidence of HCC was 0.95%, 2.18%, 5.26%, and 4.10% in patients with sustained viral suppression, viral breakthrough, suboptimal response, and the control group, respectively. The cumulative incidence of HCC in patients with sustained viral suppression was significantly lower than in patients with a suboptimal response and the controls (p=0.002 and p=0.005, respectively). In patients without cirrhosis and with decompensated cirrhosis, the preventive effects of lamivudine on the development of HCC were not observed (p=0.446 and p=0.123, respectively).
CONCLUSION: Lamivudine therapy reduced the incidence of HCC in patients with compensated cirrhosis when the viral suppression was sustained.

Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID 20471129  J Hepatol. 2010 Jul;53(1):118-25. doi: 10.1016/j.jhep.2・・・
著者: Man-Fung Yuen, Wai-Kay Seto, Danny Hoi-Fan Chow, Kit Tsui, Danny Ka-Ho Wong, Vincent Wing-Shun Ngai, Benjamin Chun-Yu Wong, James Fung, John Chi-Hang Yuen, Ching-Lung Lai
雑誌名: Antivir Ther. 2007;12(8):1295-303.
Abstract/Text BACKGROUND: Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease.
METHODS: One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually.
RESULTS: Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls (P = 0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC (P = 0.024) and a greater HBV DNA reduction (P = 0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation.
CONCLUSIONS: Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.

PMID 18240869  Antivir Ther. 2007;12(8):1295-303.
著者: Akihiro Matsumoto, Eiji Tanaka, Akinori Rokuhara, Kendo Kiyosawa, Hiromitsu Kumada, Masao Omata, Kiwamu Okita, Norio Hayashi, Takeshi Okanoue, Shiro Iino, Kyuichi Tanikawa, Inuyama Hepatitis Study Group
雑誌名: Hepatol Res. 2005 Jul;32(3):173-84. doi: 10.1016/j.hepres.2005.02.006. Epub 2005 Jul 18.
Abstract/Text A retrospective survey of Japanese patients histologically diagnosed with chronic hepatitis B was conducted to determine the effectiveness of lamivudine in preventing hepatocellular carcinoma (HCC). Of the 2795 patients who satisfied criteria for analysis after treatment from any of 30 medical institutions, 657 had received lamivudine and the remaining 2138 had not. A Cox regression model with liver biopsy as the starting point revealed seven factors related to HCC: lamivudine therapy, gender, family clustering of hepatitis B, age at liver biopsy, hepatic fibrosis stage, serum albumin level, and platelet count. In a matched case-controlled study, 377 patients in a lamivudine-treated group and 377 matched patients in a non-treated group were selected based on their propensity scores. The mean follow-up period was 2.7 years in the lamivudine group and 5.3 years in the control group. In the lamivudine group, HCC occurred in four patients (1.1%) with an annual incidence rate of 0.4%/(patient/year), whereas in the control group HCC occurred in 50 patients (13.3%) for a rate of 2.5%/(patient/year). A comparison of the cumulative HCC incidence between the two groups by the Kaplan-Meier method showed a significantly lower incidence of HCC in the lamivudine group (p<0.001). These findings suggest that lamivudine effectively reduces the incidence of HCC in patients with chronic hepatitis B.

PMID 16024289  Hepatol Res. 2005 Jul;32(3):173-84. doi: 10.1016/j.hepr・・・
著者: J J Y Sung, K K F Tsoi, V W S Wong, K C T Li, H L Y Chan
雑誌名: Aliment Pharmacol Ther. 2008 Nov 1;28(9):1067-77. doi: 10.1111/j.1365-2036.2008.03816.x. Epub 2008 Jul 24.
Abstract/Text BACKGROUND: Chronic hepatitis B (CHB) infection leads to development of hepatocellular carcinoma (HCC), but the effects of treatment in preventing HCC are not clear.
AIM: To study the effects of interferon (IFN) or nucleoside/tide analogue (NA) on the risk of developing HCC in CHB patients.
METHODS: Randomized trials, case-control and cohort studies were retrieved from five electronic databases and international conferences over the past 10 years. Relative risks (RRs) of HCC with or without treatment were studied.
RESULTS: Twelve studies (n = 2742) enrolling patients treated by IFN vs. control showed that the risk of HCC after treatment was reduced by 34% (RR: 0.66, 95% CI: 0.48-0.89). Benefit is more significant among patients with early cirrhosis than among those without cirrhosis. Five studies (n = 2289) compared patients treated by NA with control. The risk of HCC after treatment was reduced by 78% (RR: 0.22, 95% CI: 0.10-0.50). HBeAg-positive patients showed more significantly reduced HCC risk with treatment. Patients without cirrhosis benefited more from NA than those with cirrhosis. Resistance to NA has obviated the benefit of the treatment.
CONCLUSIONS: IFN or NA treatment significantly reduces risk of HCC. While IFN benefited patients with cirrhosis, NA benefited patients with no cirrhosis and HBeAg-positive CHB infection.

PMID 18657133  Aliment Pharmacol Ther. 2008 Nov 1;28(9):1067-77. doi: ・・・
著者: Yun-Fan Liaw, Joseph J Y Sung, Wan Cheng Chow, Geoffrey Farrell, Cha-Ze Lee, Hon Yuen, Tawesak Tanwandee, Qi-Min Tao, Kelly Shue, Oliver N Keene, Jonathan S Dixon, D Fraser Gray, Jan Sabbat, Cirrhosis Asian Lamivudine Multicentre Study Group
雑誌名: N Engl J Med. 2004 Oct 7;351(15):1521-31. doi: 10.1056/NEJMoa033364.
Abstract/Text BACKGROUND: The effectiveness of antiviral therapy in preventing disease progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis is unknown.
METHODS: Patients with chronic hepatitis B who had histologically confirmed cirrhosis or advanced fibrosis were randomly assigned in a 2:1 ratio to receive lamivudine (100 mg per day) or placebo for a maximum of five years. Of 651 patients, 436 were assigned to receive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data.
RESULTS: We randomly assigned 651 patients (98 percent Asian and 85 percent male) to receive lamivudine or placebo. The study was terminated after a median duration of treatment of 32.4 months (range, 0 to 42) owing to a significant difference between treatment groups in the number of end points reached. End points were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo (hazard ratio for disease progression, 0.45; P=0.001). The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo (hazard ratio, 0.45; P=0.02), whereas hepatocellular carcinoma occurred in 3.9 percent of those in the lamivudine group and 7.4 percent of those in the placebo group (hazard ratio, 0.49; P=0.047). Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine, and the Child-Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamivudine (7 percent vs. <1 percent). Overall, 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious adverse events.
CONCLUSIONS: Continuous treatment with lamivudine delays clinical progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma.

Copyright 2004 Massachusetts Medical Society.
PMID 15470215  N Engl J Med. 2004 Oct 7;351(15):1521-31. doi: 10.1056/・・・
著者: Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Norio Akuta, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
雑誌名: Hepatology. 2013 Jul;58(1):98-107. doi: 10.1002/hep.26180. Epub 2013 Mar 6.
Abstract/Text UNLABELLED: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agents such as lamivudine (LAM) have a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1,143 nontreated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5 years were 3.7% and 13.7% for the ETV and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% confidence interval: 0.15-0.91; P = 0.030). Both cohorts were applied in three previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of alanine aminotransferase, hepatitis B e antigen, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In sub analyses, we compared treatment effect between nucleos(t)ide analogs, which included matched LAM-treated patients without rescue therapy (n = 182). We found HCC suppression effect greater in ETV-treated (P < 0.001) than nonrescued LAM-treated (P = 0.019) cirrhosis patients when they were compared with the control group.
CONCLUSION: Long-term ETV treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC.

Copyright © 2012 American Association for the Study of Liver Diseases.
PMID 23213040  Hepatology. 2013 Jul;58(1):98-107. doi: 10.1002/hep.261・・・
著者: George Papatheodoridis, John Goulis, Spilios Manolakopoulos, Aikaterini Margariti, Xenofon Exarchos, Georgios Kokkonis, Emilia Hadziyiannis, Christos Papaioannou, Emanuel Manesis, Dimitrios Pectasides, Evangelos Akriviadis
雑誌名: J Hepatol. 2014 Jan;60(1):62-8. doi: 10.1016/j.jhep.2013.08.023. Epub 2013 Sep 6.
Abstract/Text BACKGROUND & AIMS: Serum HBsAg levels might represent an important predictor of sustained off-treatment response in HBeAg-negative chronic hepatitis B (CHB). We evaluated the changes of HBsAg and interferon-inducible protein 10 (IP10) serum levels in HBeAg-negative CHB patients treated with entecavir.
METHODS: 114 patients received entecavir for a median of 4.3 years. HBsAg levels were determined at baseline, 6 and 12 months and every year thereafter until year-4. IP10 levels were measured at baseline and annually until year-4 in 76 patients.
RESULTS: Virological remission rates were high (year-1: 94%, after year-2: 97-98%). Compared to baseline, HBsAg levels decreased by a median of 0.03, 0.13, 0.17, 0.22, and 0.32 log₁₀ IU/ml at 6 months and 1, 2, 3, and 4 years, respectively (p≤0.001 for all comparisons). The proportions of patients with HBsAg decline of ≥0.5 or ≥1 log₁₀ IU/ml were 9% or 6% at year-1 and 21% or 10% at the last visit. Median IP10 levels (pg/ml) did not change from baseline to year-1 or -2 (245 vs. 229 or 251), but increased at year-3 and -4 (275 and 323, p<0.030). HBsAg drop ≥0.5 log₁₀ was associated with baseline IP10 or IP10 >350 pg/ml (p≤0.002). HBsAg loss occurred in 4/114 (3.5%) patients or in 1/2, 3/21, and 0/91 patients with baseline HBsAg <100, 100-1000 and >1000 IU/ml, respectively (p<0.001).
CONCLUSIONS: In HBeAg-negative CHB patients, 4-year entecavir therapy decreases serum HBsAg levels, but the rate of decline is rather slow. Serum IP10 levels represent a promising predictor of HBsAg decline in this setting.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID 24012614  J Hepatol. 2014 Jan;60(1):62-8. doi: 10.1016/j.jhep.201・・・
著者: Chia-Ming Chu, Yun-Fan Liaw
雑誌名: Hepatology. 2007 May;45(5):1187-92. doi: 10.1002/hep.21612.
Abstract/Text Spontaneous hepatitis B surface antigen (HBsAg) seroclearance in chronic HBV infection has long been suggested as a rare event in high endemic areas. The prevalence of HBsAg in the general population of Taiwan, however, decreased remarkably from 15%-20% before age 40 to 5%-10% after age 60 or 70. This study aimed to reexamine the rates of HBsAg seroclearance by a long-term follow-up of 1965 hepatitis B e antibody-positive asymptomatic adult carriers. Of these, 1076 (55%) were males, the mean (+/-SD) age was 35.6+/-9.2 years and the mean follow-up was 10.8+/-5.4 years. Hepatitis relapsed in 314 patients, 0.5 to 18 (mean+/-SD=5.8+/-4.4) years after the entry. The probability of hepatitis relapse correlated positively with male sex (P<0.0001) and age at entry (P<0.0001). Serum HBsAg cleared in 245 patients at the mean age of 47.8+/-9.6 years. The cumulative probabilities of HBsAg seroclearance were 8.1% after 10 years, but increased disproportionally to 24.9% and 44.7%, respectively, after 20 and 25 years. In multivariate analysis, the probability of HBsAg seroclearance correlated positively with age at entry (P<0.0001) and sustained remission of hepatitis (P<0.0001) and marginally significantly with male sex (P=0.053). CONCLUSION: Cumulative rate of HBsAg seroclearance in asymptomatic adult carriers from high endemic areas was approximately 40% after 25 years of follow-up. The low HBsAg seroclearance rates in previous studies might be due to the relative short period of follow-up.

PMID 17465003  Hepatology. 2007 May;45(5):1187-92. doi: 10.1002/hep.21・・・
著者: Josephine Simonetti, Lisa Bulkow, Brian J McMahon, Chriss Homan, Mary Snowball, Susan Negus, James Williams, Stephen E Livingston
雑誌名: Hepatology. 2010 May;51(5):1531-7. doi: 10.1002/hep.23464.
Abstract/Text Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance. CONCLUSION: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early.

PMID 20087968  Hepatology. 2010 May;51(5):1531-7. doi: 10.1002/hep.234・・・
著者: Mariko Kobayashi, Fumitaka Suzuki, Norio Akuta, Tetsuya Hosaka, Hitomi Sezaki, Hiromi Yatsuji, Hiromi Yatsuji, Masahiro Kobayashi, Yoshiyuki Suzuki, Yasuji Arase, Kenji Ikeda, Sachiyo Watahiki, Satomi Iwasaki, Yuzo Miyakawa, Hiromitsu Kumada
雑誌名: J Med Virol. 2007 Oct;79(10):1472-7. doi: 10.1002/jmv.20994.
Abstract/Text Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age >or=50 years and low HBsAg levels (hemagglutination titer or=50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14-7.68], P = 0.028). By the method of Kaplan-Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment.

(c) 2007 Wiley-Liss, Inc.
PMID 17705186  J Med Virol. 2007 Oct;79(10):1472-7. doi: 10.1002/jmv.2・・・
著者: Jurriën G P Reijnders, Moniek J Perquin, Ningping Zhang, Bettina E Hansen, Harry L A Janssen
雑誌名: Gastroenterology. 2010 Aug;139(2):491-8. doi: 10.1053/j.gastro.2010.03.059. Epub 2010 Apr 8.
Abstract/Text BACKGROUND & AIMS: Inconsistencies in results and guideline recommendations regarding the durability of nucleos(t)ide analogue-induced hepatitis B e antigen (HBeAg) seroconversion require clarification. We studied the long-term durability of nucleos(t)ide analogue-induced HBeAg seroconversion in patients with chronic hepatitis B virus (HBV) infection.
METHODS: We performed a single-center cohort study of 132 HBeAg-positive patients who had received nucleos(t)ide analogue therapy.
RESULTS: During a median treatment duration of 26 months (range, 16-43 mo), HBeAg seroconversion occurred in 46 of 132 subjects (35%). Forty-two subjects (91%) had follow-up evaluation after HBeAg seroconversion. During a median follow-up period of 59 months (range, 28-103 mo) after HBeAg seroconversion, 13 of 42 patients (31%) showed a durable remission (defined as HBeAg negative and HBV-DNA level<10,000 copies/mL). Overall, 33 of 42 subjects (79%) continued therapy after HBeAg seroconversion; of these, 22 (67%) showed serologic and/or virologic recurrence. Nine of 42 subjects (21%) discontinued therapy after HBeAg seroconversion and at least 6 months of consolidation therapy. Only 2 patients showed a durable response in the absence of therapy. Disease recurrence in patients who continued therapy after HBeAg seroconversion was preceded by the development of resistance (80% of these patients); resistance only occurred in subjects given lamivudine monotherapy. In contrast, recurrence after treatment discontinuation or noncompliance was observed in all patients given nucleos(t)ide analogues.
CONCLUSIONS: Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection. Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary.

Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 20381492  Gastroenterology. 2010 Aug;139(2):491-8. doi: 10.1053/j・・・
著者: Feng Liu, Lei Wang, Xiao Ying Li, You De Liu, Jing Bo Wang, Zhao Hua Zhang, Yao Zong Wang
雑誌名: J Gastroenterol Hepatol. 2011 Mar;26(3):456-60. doi: 10.1111/j.1440-1746.2010.06492.x.
Abstract/Text BACKGROUND AND AIMS: Lamivudine, a nucleoside analog, is commonly used for treatment of chronic hepatitis B (CHB) but its durability of effectiveness after withdrawal is still uncertain. This study was designed to assess the durability of lamivudine treatment with stringent cessation criteria in hepatitis B e antigen (HBeAg)-negative patients and to explore potential predictive factors.
METHODS: Sixty one HBeAg-negative CHB patients who had received lamivudine for at least 24 months and had maintained undetectable serum hepatitis B virus (HBV) DNA plus normal alanine aminotransferase for ≥ 18 months before withdrawal were included. They were followed up monthly during the first 4 months and at 3-month or 6-month intervals thereafter. Relapse was defined as serum HBV DNA ≥ 10(4) copies/mL.
RESULTS: Thirty one of 61 patients relapsed during follow-up, over 90% occurred within 18 months after lamivudine withdrawal. Cumulative relapse rates at months 6, 12, 24, 36, 48 and 60 were 26.2%, 43.6%, 49.7%, 52.1%, 56.1% and 56.1%, respectively. Cox regression revealed that age was the only predictive factor for relapse, with lower relapse rates found in younger patients. Hepatitis B surface antigen (HBsAg) turned negative in eight patients, and none of them relapsed during follow-up.
CONCLUSION: Effectiveness of lamivudine treatment is not durable in HBeAg-negative CHB patients even when stringent cessation criteria are adopted, with the exception of patients aged ≤ 20 years. The ideal end point of lamivudine treatment is clearance of serum HBsAg.

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID 21332542  J Gastroenterol Hepatol. 2011 Mar;26(3):456-60. doi: 10・・・
著者: Akihiro Matsumoto, Eiji Tanaka, Yoshiyuki Suzuki, Mariko Kobayashi, Yasuhito Tanaka, Noboru Shinkai, Shuhei Hige, Hiroshi Yatsuhashi, Shinya Nagaoka, Kazuaki Chayama, Masataka Tsuge, Osamu Yokosuka, Fumio Imazeki, Shuhei Nishiguchi, Masaki Saito, Kei Fujiwara, Nobuyuki Torii, Naoki Hiramatsu, Yoshiyasu Karino, Hiromitsu Kumada
雑誌名: Hepatol Res. 2012 Feb;42(2):139-49. doi: 10.1111/j.1872-034X.2011.00910.x. Epub 2011 Nov 22.
Abstract/Text AIM:   The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately.
METHODS:   A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL.
RESULTS:   Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core-related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis.
CONCLUSIONS:   It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core-related antigens are also significant factors independently associated with relapse of hepatitis.

© 2011 The Japan Society of Hepatology.
PMID 22103237  Hepatol Res. 2012 Feb;42(2):139-49. doi: 10.1111/j.1872・・・
著者: Masataka Tsuge, Eisuke Murakami, Michio Imamura, Hiromi Abe, Daiki Miki, Nobuhiko Hiraga, Shoichi Takahashi, Hidenori Ochi, C Nelson Hayes, Hiroyuki Ginba, Kazuhiro Matsuyama, Hiroiku Kawakami, Kazuaki Chayama
雑誌名: J Gastroenterol. 2013 Oct;48(10):1188-204. doi: 10.1007/s00535-012-0737-2. Epub 2013 Feb 9.
Abstract/Text BACKGROUND: Treatment for chronic hepatitis B has improved drastically with the use of nucleot(s)ide analogues (NAs). However, NA therapy typically fails to eliminate Hepatitis B virus (HBV) completely, and it is difficult to discontinue these therapies. We previously demonstrated that NA therapy induced immature viral particles, including HBV RNA in sera of chronic hepatitis B patients. In the study reported here, we analyzed the association between HBV RNA titer and the recurrence rate of hepatitis after discontinuation of NA therapy.
METHODS: The study cohort comprised 36 patients who had discontinued NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by real time PCR and statistical analyses were performed using clinical data and HBV markers.
RESULTS: At 24 weeks after discontinuation of NA therapy, HBV DNA rebound was observed in 19 of the 36 patients (52.8 %), and alanine aminotransferase (ALT) rebound was observed in 12 of 36 patients (33.3 %). Multivariate statistical analysis was used to identify factors predictive of HBV DNA rebound. The HBV DNA + RNA titer following 3 months of treatment was significantly associated with HBV DNA rebound [P = 0.043, odds ratio (OR) 9.474, 95 % confidence interval (CI) 1.069-83.957)]. Absence of hepatitis B e antigen (HBeAg) at the end of treatment was significantly associated with ALT rebound (P = 0.003, OR 13.500, 95 % CI 2.473-73.705). In HBeAg-positive patients, the HBV DNA + RNA titer after 3 months of treatment was marginally associated with ALT rebound (P = 0.050, OR 8.032, 95 % CI 0.997-64.683).
CONCLUSIONS: Monitoring of serum HBV DNA + RNA levels may be a useful method for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.

PMID 23397114  J Gastroenterol. 2013 Oct;48(10):1188-204. doi: 10.1007・・・
著者: Julie A Sheldon, Angélica Corral, Berta Rodés, Stefan Mauss, Juergen Rockstroh, Florian Berger, Carolynne Schwarze-Zander, Vincent Soriano
雑誌名: AIDS. 2005 Nov 18;19(17):2036-8.
Abstract/Text Seven antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir for longer than 6 months were assessed. Using bulk population sequencing and a sensitive limiting dilution analysis, the selection of K65R or other resistance mutations did not occur in HIV, suggesting that adefovir can be confidently used as hepatitis B virus (HBV) therapy in HIV/HBV-co-infected patients who do not require antiretroviral therapy.

PMID 16260913  AIDS. 2005 Nov 18;19(17):2036-8.
著者: Kazuhiko Koike, Yoshimi Kikuchi, Michio Kato, Junki Takamatsu, Yoshizumi Shintani, Takeya Tsutsumi, Hajime Fujie, Hideyuki Miyoshi, Kyoji Moriya, Hiroshi Yotsuyanagi
雑誌名: Hepatol Res. 2008 Mar;38(3):310-4. doi: 10.1111/j.1872-034X.2007.00263.x. Epub 2007 Sep 17.
Abstract/Text Patients with HIV infection are frequently infected with hepatitis viruses, which are presently the major cause of mortality in HIV-infected patients after the widespread use of highly active antiretrovirus therapy. We previously reported that approximately 20% of HIV-positive Japanese patients were also infected with hepatitis C virus (HCV). Hepatitis B virus (HBV) infection may also be an impediment to a good course of treatment for HIV-infected patients, because of recurrent liver injuries and a common effectiveness of some anti-HIV drugs on HBV replication. However, the status of co-infection with HIV and HBV in Japan is unclear. We conducted a nationwide survey to determine the prevalence of HIV-HBV co-infection by distributing a questionnaire to the hospitals belonging to the HIV/AIDS Network of Japan. Among the 5998patients reported to be HIV positive, 377 (6.4%) were positive for the hepatitis B surface antigen. Homosexual men accounted for two-thirds (70.8%) of the HIV-HBV co-infected patients, distinct from HIV-HCV co-infection in Japan in which most of the HIV-HCV co-infected patients were recipients of blood products. One-third of HIV-HBV co-infected patients had elevated serum alanine aminotransferase levels at least once during the 1-year observation period. In conclusion, some HIV-infected Japanese patients also have HBV infection and liver disease. A detailed analysis of the progression and activity of liver disease in co-infected patients is needed.

PMID 17877726  Hepatol Res. 2008 Mar;38(3):310-4. doi: 10.1111/j.1872-・・・
著者: Kojiro Michitaka, Norio Horiike, Yan Chen, Tran Nhu Duong, Ichiro Konishi, Toshie Mashiba, Yoshio Tokumoto, Yoichi Hiasa, Yasuhito Tanaka, Masashi Mizokami, Morikazu Onji
雑誌名: Intern Med. 2004 Aug;43(8):696-9.
Abstract/Text A 12-year-old girl with Gianotti-Crosti syndrome caused by hepatitis B virus (HBV) infection was admitted due to eruption on her extremities. Laboratory findings revealed elevation of transaminase, positivity for HB surface antigen (HBsAg), and an IgM type anti-HB core. The eruption and level of transaminase improved, and HBsAg became negative within 2 months of onset. Analysis of the virus revealed it to be genotype D with a genomic length of 3,182 bases and the HBsAg serotype was ayw3, which is very rare in Japan. The possible relationship between Gianotti-Crosti syndrome and HBV genotype D infection is discussed.

PMID 15468968  Intern Med. 2004 Aug;43(8):696-9.
著者: Kojiro Michitaka, Yasuhito Tanaka, Norio Horiike, Tran Nhu Duong, Yan Chen, Kana Matsuura, Yoichi Hiasa, Masashi Mizokami, Morikazu Onji
雑誌名: J Med Virol. 2006 Jan;78(1):44-52. doi: 10.1002/jmv.20502.
Abstract/Text The major hepatitis B virus (HBV) genotypes in Japan are B and C. HBV genotype D (HBV/D), however, is widespread in a small area of Western Japan, where the Gianotti-Crosti syndrome caused by HBV subtype ayw, which is suspected to be HBV/D, was endemic in the 1970s. The aim of the study was to elucidate its origin, time of transmission, and spread in this area. Genotyping of HBV-DNA was done in 363 patients with HBV infection. The year of birth was checked in patients with HBV/D. The full genome sequences of 20 HBV/D strains, 2 of which were obtained from a single carrier with a 19-year-interval, were analyzed. An evolutionary rate, the date of the most recent common ancestor, and the effective number of HBV/D infections were calculated. Fifty-two of 363 patients were infected with HBV/D, and 39 were born in 1970s. In a phylogenetic tree, the 20 HBV/D strains produced a definite cluster, and the evolutionary rate was calculated to be 5.4 x 10(-5) nucleotide substitutions/site/year. The root of the tree was estimated to be in approximately 1,900 and began to spread from the 1940s, leading to a rapid increase of infected patients in the 1970s. From these results, it is suspected that HBV/D was likely transmitted to the area investigated approximately 100 years ago and then spread widely in the 1970s. From the history of the area and the genetic analysis, HBV/D in this area was speculated to be of Russian origin.

PMID 16299716  J Med Virol. 2006 Jan;78(1):44-52. doi: 10.1002/jmv.205・・・
著者: B Dikici, H Uzun, C Konca, H Kocamaz, S Yel
雑誌名: Adv Med Sci. 2008;53(2):338-40. doi: 10.2478/v10039-008-0013-0.
Abstract/Text Gianotti-Crosti syndrome (papular acrodermatitis of childhood), which was first described in 1955, is a nonspecific rash that usually consists of the abrupt onset of pink flesh coloring, smooth or lichenoid, flat-topped papules. It was first related to hepatitis B virus (HBV) infection; however, cases not associated with HBV infection were reported as well. Although a type of delayed hypersensitivity reaction is speculated as a cause, exact pathogenesis still remains unclear. The prognosis is favorable and successful management relies upon general supportive and symptomatic care. We report a seven-year-old boy diagnosed with Gianotti-Crosti syndrome with monomorphous papules on his cheeks, buttocks and extremities associated with hepatitis B virus infection.

PMID 18614441  Adv Med Sci. 2008;53(2):338-40. doi: 10.2478/v10039-008・・・
著者: V Turhan, N Ardic, B Besirbellioglu, T Dogru
雑誌名: Ir J Med Sci. 2005 Jul-Sep;174(3):92-4.
Abstract/Text BACKGROUND: Gianotti-Crosti Syndrome (GCS) is a characteristic cutaneous eruption following a viral infection. Incidence peaks in early childhood and the syndrome rarely occurs in adulthood. Hepatitis associated with GCS is usually anicteric and acute form.
AIM: To report an adult with GCS associated with HBV infection and presenting icteric progress.
METHODS: The clinical features of the GCS case associated with HBV infection were evaluated.
RESULT: The cutaneous lesions disappeared completely on the 61st day and clearance for HBsAg was also observed.
CONCLUSION: GCS may be seen in adults and may be associated with icteric HBV infection.

PMID 16285348  Ir J Med Sci. 2005 Jul-Sep;174(3):92-4.
著者: E Iwanami, M Yano, M Koga, S Shirahama, T Tsuda
雑誌名: J Gastroenterol Hepatol. 1993 Nov-Dec;8(6):565-8.
Abstract/Text Hepatitis B virus (HBV) carriers and patients with acute hepatitis B living in the Kamigoto islands, a part of Japan with a high incidence of HBV carriage, were retrospectively tested for serum anti-hepatitis D virus (anti-HDV) and they were compared with the inhabitants of Oita City (an area with an average HBV carriage rate). The prevalence of anti-HDV in HBV-infected individuals was 8.3% (42/507) in Kamigoto and 0% (0/101) in Oita City. With one exception, all of the positive serum samples in Kamigoto were collected before 1986, and the mean age of the positive individuals was significantly younger than that of the negative individuals (P < 0.005). Among the 42 anti-HDV-positive patients, nine (21%) had definite liver disease. The route of infection was uncertain in most cases (i.e. sporadic), but two pairs of mothers and children were detected. Although the prevalence of anti-HDV positivity in Japan has been reported to be very low (about 1% or less), the present investigation showed that the local spread of HDV infection in Kamigoto occurred on a minor scale up to 1986. The infections presumably resulted from the closed environment and the high incidence of HBV carriage in these islands. Accordingly, there could be a considerable risk of the outbreak of HDV infection in the future under similar conditions, even in countries where the disease has never been detected previously.

PMID 8280845  J Gastroenterol Hepatol. 1993 Nov-Dec;8(6):565-8.
著者: Y Arakawa, M Moriyama, M Taira, N Hayashi, N Tanaka, H Okubo, M Sugitani
雑誌名: J Viral Hepat. 2000 Sep;7(5):375-81.
Abstract/Text The present investigation attempted to determine the exact prevalence of hepatitis D virus (HDV) infection among inhabitants of Miyako Island (a remote island in the Okinawa Prefecture) and the molecular characteristics of the HDV genome that was isolated. Among the 4728 inhabitants, 375 (7.9%) were hepatitis B surface antigen (HBsAg) positive. Antibody to HDV (anti-HDV) was present in 32 (8. 5%) of these 375 subjects, and liver function tests were normal in most subjects. The presence of HDV RNA was analysed by nested polymerase chain reaction (PCR). Thirteen out of the 32 anti-HDV antibody-positive subjects were HDV RNA positive. Thus, 3.5% of HBsAg-positive subjects on Miyako Island were HDV RNA positive. Among the HDV RNA-positive subjects, liver function tests were within normal limits or were mildly abnormal. Nucleotide sequence analysis revealed that the HDV genomes on Miyako Island were similar to the Japanese and Taiwan isolates of HDV genotype II. Taiwan is geographically close to Miyako Island. Even though the races are different, a geographical factor was revealed to be significant with regard to HDV infection, which was spread in a closed environment.

PMID 10971826  J Viral Hepat. 2000 Sep;7(5):375-81.

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