Author: Flisiak, Robert ; Dobrowolska, Krystyna ; Janczewska, Ewa ; Lorenc, Beata ; Zarębska‐Michaluk, Dorota ; Jaroszewicz, Jerzy ; Mazur, Włodzimierz ; Piekarska, Anna ; Krygier, Rafał ; Sobala‐Szczygieł, Barbara ; Parfieniuk‐Kowerda, Anna ; Sitko, Marek ; Janocha‐Litwin, Justyna ; Socha, Łukasz

ABSTRACTTo date, the effectiveness of direct‐acting antivirals (DAAs) discontinued before 4 weeks has not been analysed in routine clinical practice. The study aimed to determine whether such a short therapy will enable achieving a sustained virological response under real‐world experience. The study population of 97 patients who discontinued DAA therapy and had data enabling analysis of patient and disease characteristics, and assessment of treatment effectiveness was selected from 16,815 patients registered in the EpiTer‐2 database. The most common reason for discontinuation was hepatic decompensation (20.6%) or the patient's personal decision (18.6%). Patients who discontinued treatment were significantly older, more frequently therapy‐experienced, more likely to have cirrhosis, a history of decompensation and a Child–Pugh B or C classification than those who completed treatment. SVR was achieved by 93.5% of patients who discontinued treatment after 4 weeks, 60.9% if discontinued at 3 or 4 week and 33.3% at Week 1 or 2. Patients receiving pangenotypic but not genotype‐specific treatment who discontinued after 4 weeks were as likely to achieve SVR as those who completed therapy. Patients who responded to treatment that lasted no longer than 2 weeks had a low baseline viral load (<400,000 IU/mL). Despite discontinuation of therapy after Week 4, the chances of SVR are high. Very early discontinuation does not preclude therapeutic success, especially in patients with low baseline viral load.

01 Nov 2024·Journal of Hepatology

Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals

Article

Author: Choi, In Ah ; Koh, June-Young ; Lee, Eun Young ; Park, Su-Hyung ; Lee, Ha Seok ; Ko, Yun Yeong ; Jung, Min Kyung ; Shin, Eui-Cheol ; Kim, Won ; Lee, Jeong Seok ; Kim, Hyung-Don ; Park, Jun Yong ; Lee, Dong Hyeon ; Jeong, Hye Won ; Kim, So-Young ; Choi, Seong Jin

BACKGROUND & AIMSChronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment.METHODSPatients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis.RESULTSThe Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance.CONCLUSIONSOverall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection.IMPACT AND IMPLICATIONSDuring chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.

01 Nov 2024·Liver International

Viral eradication reduces all‐cause mortality in patients with chronic hepatitis C virus infection who had received direct‐acting antiviral therapy

Article

Author: Kobashi, Haruhiko ; Kurosaki, Masayuki ; Fujii, Hideki ; Izumi, Namiki ; Tada, Toshifumi ; Yasui, Yutaka ; Kumada, Takashi ; Okada, Kazuhiko ; Koshiyama, Yuichi ; Narita, Ryoichi ; Mitsuda, Akeri ; Nakamura, Shinichiro ; Nonogi, Michiko ; Shigeno, Masaya ; Kasai, Toyotaka ; Ishii, Toru ; Uchida, Yasushi ; Tsuji, Keiji ; Yasuda, Satoshi ; Ogawa, Chikara ; Yoshida, Hideo ; Marusawa, Hiroyuki ; Morita, Atsuhiro ; Tamaki, Nobuharu ; Okamoto, Eisuke ; Kondo, Masahiko ; Mori, Nami ; Hasebe, Chitomi ; Ochi, Hironori ; Toyoda, Hidenori ; Urawa, Naohito ; Matsushita, Tomomichi ; Akahane, Takehiro ; Kubotsu, Yoshihito

AbstractBackground and AimsThe impact of hepatitis C virus (HCV) eradication via direct‐acting antiviral (DAA) therapy on overall mortality, particularly non‐liver‐related mortality, is understudied.MethodsWe recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non‐SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all‐cause mortality, including non‐liver‐related diseases, were investigated.ResultsOf the 4180 patients, 592 died during the follow‐up period. In the SVR group, the mortality rates from liver‐related and non‐liver‐related diseases were 16.5% and 83.5%, respectively. Compared to the non‐SVR group, mortality rates from liver‐related and non‐liver‐related diseases were 50.1% and 49.9%, respectively (p < .001). In non‐cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver‐related (hazard ratio [HR], .251; 95% confidence interval [CI], .092–.686) and non‐liver‐related (HR, .641; 95% CI, .415–.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver‐related mortality (HR, .151; 95% CI, .081–.279). In propensity score‐matched patients, the eradication of HCV (SVR group) decreased both liver‐related (p < .001) and non‐liver‐related mortality (p = .008) rates compared to persistent HCV infection (non‐SVR group).ConclusionsThe elimination of HCV via DAA therapy reduced not only liver‐related mortality but also non‐liver‐related mortality in patients with chronic HCV.

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