Chronische Hepatitis-B-Virusinfektion: aktuelle und zukünftige Therapieansätze
Tóm tắt
Zur Therapie der chronischen Hepatitis-B-Virus-(HBV-)Infektion stehen aktuell pegyliertes Interferon-Alpha und Nucleosid‑/Nucleotidanaloga (Entecavir und Tenofovir) zur Verfügung. Diese Medikamente ermöglichen eine Virussuppression und eine Normalisierung des Leberenzyms Glutamat-Pyruvat-Transaminase (GPT) und verhindern ein Fortschreiten der Lebererkrankung. Zahlreiche noch in klinischer Entwicklung befindliche Therapiestrategien haben jedoch eine funktionelle Heilung zum Ziel. Dabei soll erreicht werden, dass das HBV-Hüllprotein HBsAg im Blutserum nicht mehr nachweisbar ist („ausgeheilte“ Hepatitis B). Der vorliegende Beitrag gibt eine Übersicht über aktuelle und mögliche zukünftige antivirale Therapien gegen die chronische HBV-Infektion. Als Grundlage diente eine Literaturrecherche unter besonderer Berücksichtigung der aktuellen Leitlinien sowie aktueller Kongressbeiträge. Die aktuell verfügbaren antiviralen Therapien führen nur sehr selten zur Elimination von HBsAg (funktionelle Heilung). Auch ist bisher weitgehend unklar, bei welchen Patienten ein Absetzen der Langzeittherapie mit Entecavir bzw. Tenofovir sinnvoll ist. Neue Therapiestrategien in klinischer Entwicklung führen bei einem höheren Anteil der Patienten zur funktionellen Heilung. Wahrscheinlich ist aber eine Kombination mehrerer antiviraler Strategien erforderlich, um die funktionelle Heilung für die Mehrheit der Patienten zu erreichen. Eine solche Therapie kann voraussichtlich in den nächsten 5–10 Jahren vorliegen.
Tài liệu tham khảo
Stanaway JD, Flaxman AD, Naghavi M et al (2016) The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet 388:1081–1088
Cornberg M, Sandmann L, Protzer U et al (2021) S3-Leitlinie der Deutschen Gesellschaft fur Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion (AWMF-Register-Nr. 021-11). Z Gastroenterol 59:691–776
Chang TT, Liaw YF, Wu SS et al (2010) Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52:886–893
Marcellin P, Gane E, Buti M et al (2013) Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381:468–475
European Association for the Study of the Liver (2017) EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 67:370–398
Buti M, Gane E, Seto WK et al (2016) Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 1:196–206
Toyoda H, Leong J, Landis C et al (2021) Treatment and renal outcomes up to 96 weeks after tenofovir alafenamide switch from tenofovir disoproxil fumarate in routine practice. Hepatology 74:656–666
Papatheodoridis GV, Idilman R, Dalekos GN et al (2017) The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology 66:1444–1453
Choi J, Kim HJ, Lee J et al (2019) Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. JAMA Oncol 5:30–36
Choi WM, Choi J, Lim YS (2021) Effects of tenofovir vs entecavir on risk of hepatocellular carcinoma in patients with chronic HBV infection: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 19:246–258.e9
Yip TC, Wong VW, Chan HL et al (2020) Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China. Gastroenterology 158:215–225
Lee SW, Kwon JH, Lee HL et al (2020) Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naive patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis. Gut 69:1301–1308
Na JE, Sinn DH, Lee JH et al (2021) Efficacy of entecavir versus tenofovir in preventing hepatocellular carcinoma in patients with chronic hepatitis B with maintained virologic response. J Viral Hepat 28:1392–1399
Pol S (2021) Similar 5‑year HCC occurrence in tenofovir- and entecavir-treated HBV chronic infection in the French AFEF/ANRS CO22 Hepather cohort. Aliment Pharmacol Ther 53:616–629
van Bömmel F, Stein K, Heyne R et al (2021) Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial. J Hepatol 73:S118
Berg T, Lampertico P (2021) The times they are a‑changing—a refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol 75:474–480
Jourdain G, Ngo-Giang-Huong N, Harrison L et al (2018) Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med 378:911–923
Pan CQ, Duan Z, Dai E et al (2016) Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 374:2324–2334
Choi J, Yoo S, Lim YS (2021) Comparison of long-term clinical outcomes between spontaneous and therapy-induced HBsAg seroclearance. Hepatology 73:2155–2166
Bartenschlager R, Urban S, Protzer U (2019) Towards curative therapy of chronic viral hepatitis. Z Gastroenterol 57:61–73
Roca Suarez AA, Testoni B, Zoulim F (2021) HBV 2021: new therapeutic strategies against an old foe. Liver Int 41:S15–S23
Wedemeyer H, Schoneweis K, Bogomolov PO et al (2019) Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in combination with PEG-interferon alpha 2a in patients with chronic HBV/HDV co-infection. J Hepatol 70:E81
Asselah T, Arama SS, Bogomolov P et al (2021) Safety and efficacy of bulevirtide monotherapy and in combination withpPeginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. J Hepatol 75:S291
Zoulim F, Lenz O, Vandenbossche JJ et al (2020) JNJ-56136379, an HBV capsid assembly modulator, is well-tolerated and has antiviral activity in a phase 1 study of patients with chronic infection. Gastroenterology 159:521–533
Bazinet M, Pantea V, Placinta G et al (2020) Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naive to nucleos(t)ide therapy. Gastroenterology 158:2180–2194
Gane E, Locarnini S, Lim T et al (2020) Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen suppression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment. J Hepatol 73:S20
Lang J, Neumann-Haefelin C, Thimme R (2019) Immunological cure of HBV infection. Hepatol Int 13:113–124
Heim K, Binder B, Sagar et al (2020) TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut 70:1550–1560
Gane EJ, Kim HJ, Visvanathan K et al (2021) Safety, pharmacokinetics, and pharmacodynamics of the oral TLR8 agonist selgantolimod in chronic hepatitis B. Hepatology 74:1737–1749
Boni C, Janssen HLA, Rossi M et al (2019) Combined GS-4774 and tenofovir therapy can improve HBV-specific T‑cell responses in patients with chronic hepatitis. Gastroenterology 157:227–241
Zoulim F, Fournier C, Habersetzer F et al (2020) Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial. Hum Vaccin Immunother 16:388–399