Follow‐up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin‐free treatment

Kozbial, K; Moser, Stephan; Al‐Zoairy, Ramona; Schwarzer, R; Datz, Christian; Stauber, Rudolf; Laferl, Hermann; Straßer, Michael; Beinhardt, Sandra; Stättermayer, Albert Friedrich; Gschwantler, Michael; Zoller, Heinz; Maieron, A; Graziadei, Ivo; Trauner, Michael; Steindl–Munda, Petra; Hofer, Harald; Ferenci, Péter

doi:10.1111/liv.13629

Cited by 59 publications

(63 citation statements)

References 36 publications

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“…Along the same line are the strong relationships found in regression analyses between HCC occurrence or recurrence and factors related to advanced fibrotic disease and severe portal hypertension, such as splenic size and low PVv. This is consistent with the suggestion put forward by Kozbial et al that the risk of developing HCC is linked with advanced stage of cirrhosis of patients treated with DAAs . Much less evident was the relationship with liver function, given that albumin level was related to de novo HCC occurrence only in univariate analysis.…”

Section: Discussionsupporting

confidence: 91%

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

et al. 2018

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Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

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Section: Discussionsupporting

confidence: 91%

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

et al. 2018

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“…We feel that drawing any definite conclusion on this topic on the basis of our data may be premature and that longer follow‐up of larger cohorts is needed to confirm or confute these findings, yet we feel that patients who show a lack of decrease in liver stiffness after viral clearance may deserve particular attention, as in our series 20% of patients with this behaviour developed HCC during 1‐year follow‐up, and there is evidence showing that portal hypertension is an independent predictor of HCC development . Moreover, our results are consistent with those very recently reported in a study with a similar follow‐up (ie, 65.6 weeks after the end of successful DAA treatment) showing no liver‐related events in 158 patients with F3 fibrosis, while 4.7% of the 317 patients with compensated cirrhosis had a liver‐related event that included both decompensation and development of HCC; likewise, a very large study carried out in our Country, similar data showing that the actual rate of HCC may be reduced by means of DAA treatment, though a residual risk still exists …”

Section: Discussionsupporting

confidence: 89%

Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals

Giannini

Crespi

Demarzo

et al. 2018

Eur J Clin Investigation

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Background The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease after sustained virological response (SVR) to direct‐acting antivirals (DAAs) has not yet been completely depicted. We aimed to assess the clinical, biochemical and instrumental outcome of patients with advanced, compensated chronic HCV‐related liver disease with DAA‐induced SVR to DAAs and who had at least 1‐year follow‐up. Materials and methods Fifty‐two patients with cirrhosis (n = 27) and fibrosis stage F3 (n = 25) followed up for a median of 60 weeks after successful DAA treatment were included. Laboratory work‐up, including APRI and FIB‐4 scores, liver transient elastography and measurement of the spleen bi‐polar diameter were carried out before treatment and at the end of follow‐up. Results Liver stiffness decreased (P < 0.0001) from a median baseline of 15.2 kPa (12.0‐20.0) to 9.3 kPa (7.5‐12.0) at follow‐up. A liver stiffness value suggestive of the presence (ie, ≥21.0 kPa) of clinically significant portal hypertension was found in 13 patients (25.0%) at baseline and in seven patients (13.5%) at follow‐up (P = 0.037). Both APRI (P < 0.0001) and FIB‐4 score (P = 0.025) progressively decreased, while platelet count increased (143 × 109/L [117‐176] to 153 × 109/L [139‐186], P = 0.003), and spleen bi‐polar diameter decreased (120 mm [112‐123] to 110 mm [102‐116], P = 0.0009) from baseline to the end of follow‐up. Conclusions In patients advanced, compensated chronic liver disease, liver stiffness significantly improves in the long‐term after SVR, and this improvement is accompanied by an amelioration of indirect indices of liver fibrosis and function, and by a decrease in parameters of portal hypertension.

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“…However, it was seen mostly in patients with advanced liver disease. Rates of hepatic decompensations (8.3%), need for liver transplantation (1.5%) as well as deaths (2.0%) during the follow‐up period were similar to those observed by Kozbial et al −9.1%, 1.2%, and 2.2% respectively. A similar death rate was noticed in large German Hepatitis C‐Registry of patients with advanced liver disease…”

Section: Discussionsupporting

confidence: 85%

“…In contrast, there were no relapses among 232 patients treated with a more potent regimen of daclatasvir and sofosbuvir. No relapses were also observed in another study carried out by Kozbial et al in 551 patients treated with different but potent DAA combinations. Unfortunately, the range of follow‐up in these 2 studies varied between 11 and 239 or 13 and 155 weeks respectively, so at least in some individuals risk of relapse after a monitored period cannot be excluded due to short observation periods .…”

Section: Discussionsupporting

confidence: 65%

“…No relapses were also observed in another study carried out by Kozbial et al in 551 patients treated with different but potent DAA combinations. Unfortunately, the range of follow‐up in these 2 studies varied between 11 and 239 or 13 and 155 weeks respectively, so at least in some individuals risk of relapse after a monitored period cannot be excluded due to short observation periods . In recently presented data from 1393 patients who achieved SVR in clinical trials with sofosbuvir‐containing regimens, relapse occurred in one patient only.…”

Section: Discussionsupporting

confidence: 65%

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Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in the AMBER, real‐world experience study

Flisiak

Janczewska

Łucejko

et al. 2018

Journal of Viral Hepatitis

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We followed for 2 years patients treated with direct-acting agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction in liver stiffness (LS) and risk of hepatocellular carcinoma (HCC). The study included patients from 16 hepatologic centres involved in the AMBER, investigator-initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. A total of 204 patients among 209 from the primary study were enrolled, 200 with available testing at 2-year follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 nonresponders retreated). During 2yFU, 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post-treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses were lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, 2-year follow-up confirmed durability of virologic response after treatment of HCV infection with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics that support the need for longer than 2-year monitoring for possible disease progression.

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Follow‐up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin‐free treatment

Cited by 59 publications

References 36 publications

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals

Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in the AMBER, real‐world experience study

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