Sodium taurocholate cotransporting polypeptide (NTCP) polymorphisms may influence HDV RNA load and early response to bulevirtide.

BACKGROUND & AIMS: Sodium taurocholate cotransporting peptide (NTCP) genetic polymorphisms have been described, but their role in untreated and treated patients with Chronic Hepatitis Delta (CHD) remains unknown. Virological response (VR) to NTCP inhibitor Bulevirtide (BLV) was achieved at week 48 by >70% of CHD patients, but nearly 15% experienced virological nonresponse (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in CHD patients. METHODS: Untreated and BLV treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing. RESULTS: Of the 6 NTCP polymorphisms studied in 209 CHD untreated patients, carriers of rs17556915 TT/CC (N=142) compared to CT (N=67) genotype presented higher median HDV RNA levels (5.39 vs. 4.75 log10 IU/mL, p=0.004). 76 out of 209 patients receiving BLV monotherapy at 2 mg/day were evaluated at week 24 and 40 of them up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (N=43) compared to CT (N=33) carriers (5.38 vs. 4.72 log10 IU/mL, p=0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p=0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p=0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. CONCLUSIONS: The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in untreated and BLV treated patients with CHD and may contribute to identify patients with different early virological responses to BLV.

Quantification of serum HDV RNA by Robogene 2.0 in HDV patients is significantly influenced by the extraction methods.

BACKGROUND AND AIM: Management of chronic hepatitis delta (CHD) requires reliable tests for HDV RNA quantification. The aim of the study was to compare two extraction methods for the quantification of HDV RNA in untreated and bulevirtide (BLV)-treated CHD patients. METHODS: Frozen sera from untreated and BLV-treated CHD patients were tested in a single-centre study for HDV RNA levels (Robogene 2.0, Roboscreen GmbH, Leipzig, Germany; LOD 6 IU/mL) with two extraction methods: manual (INSTANT Virus RNA/DNA kit; Roboscreen GmbH, Leipzig, Germany) versus automated (EZ1 DSP Virus Kit; Qiagen, Hilden, Germany). BLV-treated patients were sampled at baseline and during therapy. RESULTS: Two hundred sixty-four sera collected from 157 CHD (139 untreated, 18 BLV-treated) patients were analysed: age 51 (28-78), 59% males, 90% of European origin, 60% cirrhotics, ALT 85 (17-889) U/L, HBsAg 3.8 (1.7-4.6) Log IU/mL, 81% HBV DNA undetectable, 98% HDV genotype 1. Median HDV RNA was 4.53 (.70-8.10) versus 3.77 (.70-6.93) Log IU/mL by manual versus automated extraction (p < .0001). Manual extraction reported similar HDV RNA levels in 31 (20%) patients, higher in 119 (76%) [+.5 and +1 log10 in 60; > +1 log10 in 59] and lower in 7 (4%). Among 18 BLV-treated patients, rates of HDV RNA < LOD significantly differed between the two assays at Weeks 16 and 24 (0% vs. 22%, p = .02; 11% vs. 44%, p = .03), but not at later timepoints. By contrast, virological response rates were similar. CONCLUSIONS: Quantification of HDV RNA by Robogene 2.0 is influenced by the extraction method, the manual extraction being 1 Log more sensitive.

Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension.

BACKGROUND & AIMS: Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown. METHODS: Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml). RESULTS: Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x103/µl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic. CONCLUSIONS: A 48-week course of BLV 2 mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH. LAY SUMMARY: Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension.

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting.

BACKGROUNDS & AIMS: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. METHODS: One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. RESULTS: Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). CONCLUSIONS: Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low.

Bridging all oral DAA therapy from wait time to post-liver transplant to improve HCV eradication?

BACKGROUND & AIMS: Recurrence of hepatitis C is a major cause of graft loss and shortened survival in patients receiving a liver transplant (LT) for end-stage hepatitis C virus (HCV) infection. The only way to improve graft and patient outcomes is a successful eradication of HCV infection by antiviral therapy either before or after transplant. This was achievable in a small proportion of recipients by IFN-based regimens, but could be obtained in the majority of them by using DAA IFN-free regimens before/after transplant. METHODS: We describe a patient with decompensated cirrhosis because of severe recurrent hepatitis C, who had a retransplant following treatment with a combination of sofosbuvir and riba virin that started during the waiting time and was carried over during both the transplant and post-transplant phases for an overall period of 24 weeks. The patient gave a written consent to receive Sofosbuvir plus Rbv therapy pre and post-transplant. RESULTS: Post-transplant serum HCV-RNA remains undetectable 24 weeks after discontinuing sofosbuvir and ribavirin (SVR24). CONCLUSIONS: Waiting for direct antiviral agents combinations, our findings not only support the use of sofosbuvir plus ribavirin as the first-line treatment in all patients on the LT waiting list, but also suggest to bridge treatment to the post-transplant period in case HCV RNA undetectability for at least 30 days has not been achieved at the time of LT.

Long-term endoscopic surveillance in HBV compensated cirrhotic patients treated with Tenofovir or Entecavir for 11 years.

BACKGROUND: Long-term administration of TDF/ETV in patients with HBV-related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown. AIM: To assess the risk of EV development/progression in this population. METHODS: A total of 186 Caucasian HBV-monoinfected compensated cirrhotics were enrolled in a long-term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time. RESULTS: At TDF/ETV start, median age was 61 years, 80% males, 60% HBV-DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low-risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11-year cumulative probability of 5.1% (95% CI 3-10%); no patient bled. Out of 161 patients without EV at baseline, the 11-year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11-year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset. CONCLUSIONS: In compensated cirrhotic patients under long-term effective TDF/ETV treatment, the 11-year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.

Directly acting antivirals are safe and effective in HCV positive patients aged 80 years and older: a multicenter real-life study.

Background: Treatment of chronic Hepatitis C with directly acting antivirals (DAAs) can bring to sustained virologic response (SVR) in approximately 95% of patients. Efficacy and safety of DAAs in aging patients has not been widely analyzed. We aimed to determine safety and efficacy of DAA-based regimens in a cohort of elderly patients in a real-life setting.Research Design and Methods: We retrospectively investigated safety and efficacy of DAAs in HCV patients of 80 years or older treated in three Hepatology Units.Results and Expert opinion: During the study period, 170 patients older than 80 years received DAAs. Their mean age was 82,3 years. The predominant HCV genotype was 1 (100 patients, 59%). Among the 93 cirrhotic patients (54,7%), 18 had CPT score > A5. Different DAAs regimens were used. Concomitant drugs were common: 163 patients (95,8%) taking at least one drug. In 11 patients, usual therapy had to be changed to start antiviral treatment. Two serious adverse events occurred. Four patients terminated treatment prematurely. In total, 45 patients (26,5%) testified mild side effects. HCV-RNA undetectability at week 12 of treatment follow-up was achieved in 168/170 patients. DAA treatment in HCV patients of 80 years or older is efficacious and safe. Drug-drug interaction should be judiciously evaluated before starting therapy.

The pattern of pegylated interferon-alpha2b and ribavirin treatment failure in cirrhotic patients depends on hepatitis C virus genotype.

BACKGROUND: Failure of anti-hepatitis C therapy encompasses both primary non-response and post-treatment relapse. Treatment failure to pegylated interferon (PEG-IFN)-alpha2b and ribavirin (RBV) largely depends upon virus genotype, but the interaction between genotype, cirrhosis and pattern of treatment failure is unclear. We aimed to assess whether cirrhosis modifies the pattern of PEG-IFN-alpha2b and RBV treatment failure. METHODS: A total of 471 treatment-naive patients with histologically proven chronic hepatitis C virus (HCV) infection (106 with cirrhosis; 185 with HCV genotype 1 [HCV-1], 157 with HCV genotype 2 [HCV-2], 92 with HCV genotype 3 [HCV-3] and 37 with HCV genotype 4 [HCV-4]) were consecutively treated with PEG-IFN-alpha2b 1.5 microg weekly and weight-based RBV. RESULTS: The sustained virological response (SVR) rates were 31% in HCV-1 and HCV-4, 80% in HCV-2 and 72% in HCV-3, and were lower in cirrhotic than in non-cirrhotic HCV-1 and HCV-4 (17% versus 36%; P=0.01), and HCV-3 (33% versus 79%; P=0.001), but not HCV-2 (69% versus 83%; P=0.1) patients. Treatment failure was the consequence of lower end-of-treatment response rates (37% versus 53%; P=0.06) plus higher post-treatment relapse rates (55% versus 31%; P=0.07) in cirrhotic HCV-1 and HCV-4 patients and higher rates of post-treatment relapse in HCV-2 (29% versus 10%; P=0.01) and HCV-3 cirrhotic patients (61% versus 12%; P<0.001). By multivariate analysis, HCV-1 and HCV-4 (odds ratio [OR] 7.44, 95% confidence interval [CI] 4.87-11.36), and cirrhosis (OR 3.00, 95% CI 1.80-5.00) were independent predictors of treatment failure. CONCLUSIONS: Cirrhosis is an important moderator of SVR, accounting for different patterns of treatment failure in patients infected with different genotypes.

Ribavirin Impairs Salivary gland function During Combination Treatment With Pegylated Interferon Alfa-2a In HEpatitis C patients.

BACKGROUND: Xerostomia is a common adverse event of unknown etiology observed during pegylated interferon (PegIFN)/Ribavirin (Rbv) treatment. OBJECTIVES: To assess the frequency and mechanisms of xerostomia during PegIFN/Rbv therapy. PATIENTS AND METHODS: Thirty-one naïve patients with chronic hepatitis C consecutively received PegIFN-α2a (180 µg/week) plus Rbv (800-1200 mg/day). The controls were 10 patients with chronic hepatitis B who received PegIFN-α2a (180 µg/week). During treatment and follow-up, all patients underwent basal and masticatory stimulated sialometry,otorhinolaryngoiatric (ORL) examination, and a questionnaire survey to subjectively assess symptoms of oral dryness. RESULTS: Twenty-seven patients on PegIFN/Rbv and 4 on PegIFN (87% vs. 40%, P = 0.006) reported xerostomia. Thirty patients on PegIFN/Rbv combination therapy and 2 patients on monotherapy had ORL signs of salivary gland hypofunction (97% vs. 20%, P < 0.0001).Mean basal (A) and stimulated (B) salivary flow rates (mL/min) progressively decreased during PegIFN/Rbv treatment (A, 0.49 at baseline vs. 0.17 at the end of treatment, P < 0.0001; B, 1.24 at baseline vs. 0.53 at the end of treatment, P = 0.0004). At week 24 following PegIFN/Rbv treatment, salivary flow rates were similar to baseline (A, 0.53 at the end of follow-up vs. 0.49 at baseline; B, 1.19 at the end of follow-up vs. 1.24 at baseline). Salivary function was unaffected in monotherapy patients. CONCLUSIONS: Rbv causes salivary gland hypofunction in hepatitis C patients receiving PegIFN/Rbv therapy, which promptly reverts to normal upon cessation of treatment.