Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Cheung, Michelle; Walker, Alex J; Hudson, B; Verma, Suman; McLauchlan, John; Mutimer, David; Brown, Ashley; Gelson, William; MacDonald, Douglas; Agarwal, Kosh; Foster, Graham R.; Irving, William L.

doi:10.1016/j.jhep.2016.06.019

Cited by 380 publications

(385 citation statements)

References 15 publications

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“…Treatment should be initiated as soon as possible in order to complete a full treatment course and achieve SVR before LT [3,4]. A benefit of SVR may be a significant improvement of liver function, leading to temporary inactivation or even delisting of selected cases [5,6] [B1]; -Treatment regimens including an NS3/4A protease inhibitor, such as Simeprevir, ritonavir-boosted Paritaprevir or Grazoprevir, are contraindicated in patients with ChildPugh B and C decompensated cirrhosis and in compensated cirrhosis with previous episodes of decompensation, because of the substantially higher protease inhibitor exposure in these patients [A1]; -Only Sofosbuvir-based regimens are recommended: 1) Sofosbuvir plus Ledipasvir, 2) Sofosbuvir plus Daclatasvir, or 3) Sofosbuvir plus Velpatasvir with daily weight-based ribavirin (RBV) (1000 or 1200 mg if body weight is <75 kg or >75 kg, respectively). RBV should be initiated at a low dose of 600 mg per day, increased subsequently depending on patient's tolerability Patients with a MELD score >18-20 in LT programs where the waiting time to transplant exceeds 6 months can be treated cautiously before LT [B1] [2,3].…”

Section: Patients With Decompensated Cirrhosis Without Hcc Awaiting Ltmentioning

confidence: 99%

Position Paper on Treatment of Hepatitis C in Romania 2017. Part Two

Gheorghe

Sporea

Iacob

et al. 2017

JGLD

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Background & Aims: Hepatitis C virus (HCV) infection is a common condition with endemic prevalence in some areas of the world. In Romania, the mean prevalence is about 3%. New treatments have become available on the market in recent years and new drugs are in the pipeline. A re-evaluation of HCV therapy was considered mandatory. The Romanian Society of Gastroenterology and Hepatology undertook this task for the practitioners of this country.Methodology: A group of recognized experts was created who screened the available literature and the major available guidelines. A list of items requiring attention was created and these were discussed and rated. Decisions were taken by consensus.Recommendations: We present here the second part of the Society’s recommendations for chronic HCV infection treatment. An agreement between experts was reached regarding the therapy of the special categories of patients infected with HCV, complications and monitoring of the therapy, follow-up of the patients who reached sustained virologic response and re-treatment of the patients with therapy failure.Conclusions: This Position Paper represents a guide for the assessment and the therapy of HCV infection. The recommendations are in concordance with other guidelines but are applied to real-life conditions in Romania. Abbreviations: CKD: Chronic kidney disease; DAAs: Direct-acting antivirals; DDIs: Drug-drug interactions; ESDL: End-stage liver disease; FCH: Fibrosing cholestatic hepatitis; GT: Genotype; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; LT: Liver transplantation; MELD score: Mayo-Clinic End-Stage Liver Disease score; PDC: Premature discontinuation; PWID: Persons who inject drugs; RASs: Resistance associated substitutions; RBV: Ribavirin; RCT: Randomized controlled trial; SAE: Serious adverse events; SRGH: Romanian Society of Gastroenterology and Hepatology; SVR: Sustained virologic response.

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Section: Patients With Decompensated Cirrhosis Without Hcc Awaiting Ltmentioning

confidence: 99%

Position Paper on Treatment of Hepatitis C in Romania 2017. Part Two

Gheorghe

Sporea

Iacob

et al. 2017

JGLD

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“…However, individuals who are chronically infected but remain untreated have the highest risk of developing liver cirrhosis and HCC. Recent clinical studies show that an HCV cure using DAA‐based antiviral therapy among patients with advanced liver cirrhosis does not eliminate HCC risk 1, 2, 3. The incidence of HCC after a viral cure with a DAA‐based therapy was found to be much higher than that of the earlier findings with an interferon (IFN)‐based antiviral therapy 4.…”

Section: Introductionmentioning

confidence: 98%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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“…Further studies showed comparable SVR rates among patients with advanced liver disease, as well as improvement in disease severity (namely improvement in MELD and CHILD scores). Such results were found early after the end of the treatment (5,6).…”

mentioning

confidence: 56%