Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C.

BACKGROUND/AIMS: Accuracy of transient elastography (TE) in hepatitis B virus (HBV) infection has not been well established. We aimed to compare the performances of TE for the assessment of liver fibrosis in patients with chronic HBV or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not alanine aminotransferase (ALT) levels would impact on the accuracy of TE. METHODS: This cross-sectional study, carried out in a single centre, included treatment-naïve patients with compensated chronic HBV or HCV infection, consecutively admitted between 2006 and 2008 for a liver biopsy and TE measurement on the same day. RESULTS: A total of 202 HBV patients and 363 HCV subjects were evaluated. Overall diagnostic accuracy of TE in the HBV group was comparable to that observed in HCV patients [area under the receiver-operating characteristics (AUROCs) 0.867 ± 0.026 vs. 0.868 ± 0.019 for predicting F ≥ 2, P = 0.975; 0.902 ± 0.029 vs. 0.894 ± 0.020 for F ≥ 3, P = 0.820; and 0.935 ± 0.024 vs. 0.947 ± 0.027 for F4, P = 0.740 respectively]. TE exhibited comparable accuracies, sensitivities, specificities, predictive values and likelihood ratios in HBV and HCV groups. AUROC analysis showed no influence of ALT levels on the performance of TE in HBV individuals. ALT-specific cut-off values did not exhibit significantly higher diagnostic performances for predicting fibrosis in HBV patients with elevated ALT. CONCLUSIONS: In HBV patients, TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis and shows similar performances as compared to HCV patients. The use of TE cut-off values adjusted to ALT level did not improve performances for estimating liver fibrosis in HBV patients.

Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.

UNLABELLED: A sustained virologic response (SVR) in patients with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin is defined as undetectable serum HCV-RNA at 24 weeks (W+24) posttreatment follow-up. Viral load outcome in patients with virological relapse (VR) has not been explored. This study evaluated whether the assessment of serum HCV-RNA 12 weeks (W+12) after the end of treatment was as relevant as W+24 to evaluate SVR in 573 patients who received combination PEG-IFN and ribavirin and had a virological response at the end of treatment. Serum HCV-RNA was measured, using a new assay based on transcription-mediated amplification (TMA) with a lowest detection limit of 5-10 IU/mL, at W+12 and W+24 after the end of treatment. VR was defined as reappearance of detectable HCV-RNA at W+24 posttreatment follow-up. The positive predictive value (PPV) of undetectable serum HCV-RNA at W+12 was evaluated to identify patients with SVR, and the viral load outcome was measured in relapse patients. At the W+24 posttreatment follow-up, 408 (71%) patients had an SVR, 181 (71.2%) were treated with PEG-IFNalpha-2a and ribavirin, and 227 (71.1%) were treated with PEG-IFNalpha-2b and ribavirin. At W+12, serum HCV-RNA was undetectable in 409 patients, and 408 patients were SVR (PPV 99.7%, 95% confidence interval 99.1-100). In relapse patients, serum HCV-RNA levels were 5.623 +/- 0.748, 4.979 +/- 0.870, and 5.216 +/- 0.758 log(10) IU/mL at baseline, W+12, and W+24, respectively. CONCLUSION: Our results show that the assessment of serum HCV-RNA 12 weeks after the end of treatment, using the highly sensitive TMA assay (PPV 99.7%), is as relevant as after 24 weeks to predict SVR and make decisions on the management of treated patients, suggesting a new definition for SVR.

Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) currently represents the major cause of liver-related death in patients with hepatitis C virus (HCV)-related cirrhosis. We assessed the influence of combination therapy on the risk of HCC, liver-related complications (ascites, variceal bleeding), and liver-related death (or liver transplantation). METHODS: Three hundred seven chronic hepatitis C patients with bridging fibrosis (n=127) or cirrhosis (n=180) were evaluated by Cox regression analysis. Sustained virological response (SVR) was defined as undetectable serum HCV RNA at 24 weeks after treatment. RESULTS: SVR developed in 33% of patients. The SVR rates were not different between patients with bridging fibrosis (37%) and those with cirrhosis (30%), p=0.186. During a median follow-up of 3.5 years (range 1-18 years) after the last treatment, the incidence rates per 100 person-years of HCC, liver-related complications, and liver-related death, were 1.24, 0.62, and 0.61 among SVR patients, respectively, and 5.85, 4.16, and 3.76 among non-SVR patients, respectively (log-rank test, p<0.001). According to multivariate analysis, non-SVR was an independent predictor of HCC (HR 3.06; 95% CI=1.12-8.39), liver-related complications (HR 4.73; 95% CI: 1.09-20.57), and liver-related death (HR 3.71; 95% CI=1.05-13.05). CONCLUSIONS: SVR is achieved in one-third of patients with HCV-related cirrhosis treated with peginterferon and ribavirin. SVR has a strong independent positive influence on the incidence of HCC and on the prognosis of these patients.

Virological response at 4 weeks to predict outcome of hepatitis C treatment with pegylated interferon and ribavirin.

BACKGROUND: Viral kinetics during therapy provides information on how to individualize treatment. To determine the benefit of assessing positive predictive values (PPVs) and negative predictive values (NPVs) of rapid virological responses (RVRs) and early virological responses (EVRs), on-treatment outcomes in chronic hepatitis C patients were examined. METHODS: A total of 408 patients (221 treatment-naive) treated with pegylated interferon-alpha2b and ribavirin were included. Hepatitis C virus (HCV) RNA was measured at baseline, 4 weeks and 12 weeks. RVR was defined as undetectable HCV RNA at 4 weeks and EVR as >/=2 log(10) decrease in HCV RNA at 12 weeks. The additive value of RVR on predicting sustained virological response (SVR) was assessed with receiver operating characteristic (ROC) curves. RESULTS: SVR, RVR and EVR were observed in 46%, 23% and 78% of patients, respectively. PPVs of RVR were 96%, 100% and 100% in treatment-naive patients, relapsers and non-responders, respectively. NPVs of failure to achieve EVR were 97%, 75% and 91%, in treatment-naive patients, relapsers and non-responders, respectively. At 4 weeks, patients with RVR had the highest probability to achieve SVR (odds ratio 44.98 in the entire population and 32.95 in treatment-naive patients). ROC curves showed the area under the ROC curve to be 0.758 versus 0.832 in the entire population and 0.795 versus 0.858 in treatment-naive patients at baseline versus week 4, respectively. CONCLUSIONS: RVR is a strong predictor of SVR (PPV>96%) and failure to achieve EVR is a strong predictor of non-SVR (NPV>75%), independent of patients' pretreatment status. Added to baseline characteristics, RVR increased the accuracy to predict SVR. The combination of RVR and EVR provided complementary information, and thus provides a key opportunity to individualize treatment and improve the benefit/risk ratio of therapy.

Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C.

BACKGROUND & AIMS: It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieved a sustained virologic response (SVR). METHODS: In this long-term follow-up study, including chronic hepatitis C patients who achieved SVR after interferon-based therapy, the presence of residual HCV RNA in serum, liver, and peripheral blood mononuclear cells (PBMCs) was assessed, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). The benefit of SVR on liver fibrosis was evaluated using the METAVIR score. RESULTS: A total of 344 patients were followed up for a median duration of 3.27 years (range, 0.50-18 y; interquartile range [IQR], 1.68-5.35 y). A total of 114 patients had a posttreatment liver tissue (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) and a total of 156 had one PBMC (median, 3.0 y; range, 0.50-18 y; IQR, 1.25-5.50 y). Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. Histologic analysis of 126 paired pretreatment and posttreatment liver biopsy specimens (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) showed that fibrosis stage was improved in 56%, stable in 32%, deteriorated in 12%. Regression of cirrhosis was observed in 9 of 14 (64%) (95% confidence interval, 39-89) patients. No cirrhosis decompensation was observed, and 3 patients developed hepatocellular carcinoma. CONCLUSIONS: In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation, in addition to fibrosis stability/improvement (88%) and cirrhosis regression (64%). The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.

Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody.

BACKGROUND/AIM: Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial. METHODS: During a long-term follow-up study, 157 patients with SVR to IFN-alpha-2b-based therapy were investigated with a transcription-mediated amplification (TMA) assay in serum. The hepatitis C virus (HCV) antibody was assessed by measuring the optical density (OD) (Axsym HCV v3.0) and the semiquantitative titres (RIBA HCV v3.0) of the HCV antibodies directed against the core, NS3, NS4 and NS5 proteins. A control group included 23 untreated patients with persistently normal serum alanine aminotransferase and detectable serum HCV-RNA. RESULTS: The median duration of follow-up was 4.0 (0-10) years. Serum HCV-RNA remained undetectable in all patients. The mean HCV antibody OD were 93 +/- 19 and 45 +/- 21 before therapy and in the last available serum sample respectively (P=0.001). There was a marked decrease in the HCV antibodies directed against the NS3, NS4 and NS5 proteins (P=0.001), while the core protein titre remained strongly positive. The 23 control patients were followed for a median of 5 (2-14) years. The mean HCV antibody OD were 65 +/- 14 and 64 +/- 19 in the first and the last measurements, respectively (NS), and HCV antibody titres for structural and non-structural proteins remained unchanged. CONCLUSION: This long-term study evaluating 157 patients demonstrated that SVR assessed by TMA is durable, and HCV antibodies were markedly decreased (mainly those directed against the non-structural proteins), emphasizing an absence of ongoing infection. These results strongly suggest that HCV infection cured in patients who achieve an SVR.

Efficacy and safety of sofosbuvir-based therapies in patients with advanced liver disease in a real-life cohort.

BACKGROUND: The combination of sofosbuvir (SOF) with ribavirin (RBV) or daclatasvir (DCV) or simeprevir (SIM) for the treatment of patients infected by chronic hepatitis C (CHC) have led to significantly increased rates of sustained virological response (SVR). However, there is only limited data regarding factors associated with treatment failure in a "real-life" cohort. PATIENTS AND METHODS: Consecutive treatment-naive and treatment-experienced patients F3-F4 were treated with SOF-based interferon-free therapy in our hospital from November 2013 to July 2015. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after cessation of therapy (SVR12). RESULTS: A total of 167 treatment-naive and 207 treatment-experienced patients were treated and followed up for 2 years (n=383). Overall, 71% were men; among them, 54% had cirrhosis and the median age was 53 years. SVR12 was achieved by 82% of the patients receiving SOF+RBV, 92% receiving SOF+DCV, and 79% receiving SOF+SIM. Metavir F4 and albumin serum were found as independent risk factors associated with treatment failure in groups receiving SOF+RBV (p=0.008 and p=0.001), SOF+DCV (p=0.038 and p=0.043), and SOF+SIM±RBV (p=0.014 and p=0.017), respectively. The most common adverse events were fatigue, nausea, headache, and anemia. Three patients discontinued the treatment due to an adverse event. CONCLUSION: These findings suggest that 12-week SOF-based regimen plus RBV or DCV or SIM is an efficacious and well-tolerated treatment in CHC patients with fibrosis stage F3-F4. Patients, who display risk factors for cirrhosis, should be referred to an experienced viral hepatitis center.

The current status of antiviral therapy of chronic hepatitis B.

In recent years, marked progress has been made in the treatment of chronic viral hepatitis. Recent studies suggest that pegylated interferons (PEG IFNs) are more effective than standard IFNs in the treatment of chronic hepatitis B. So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short-term efficacy. However, long-term efficacy needs to be addressed and different schedules of combination, for example sequential, need to be evaluated. A number of nucleoside analogues, with favourable toxicity profiles and a promise of increased effectiveness against HBV, are in various stages of clinical development. Entecavir has recently been approved in the USA. The future of chronic hepatitis B therapy seems to be in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have a potent antiviral effect, an excellent safety profile and the duration of therapy should be limited. Indeed, the concept of combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far there are few data available and no combination therapy demonstrated a clear benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.