Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin

Background & Aims: Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. Methods: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. Results: Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). Conclusions: Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia

Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models

The combination of pegylated interferon (PEG-IFN) and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon-stimulated genes (ISGs) in patients treated for hepatitis C virus (HCV) infection. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was studied. Similar to interferon (IFN)-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative polymerase chain reaction assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IFN regulatory factors 7 and 9, are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with IFN-α, induction of specific ISGs is synergistic when compared with either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with IFN signaling and intracellular double-stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and nuclear factor κB pathways in the action of ribavirin

A bivalent HCV peptide vaccine elicits pan-genotypic neutralizing antibodies in mice

© 2020 Elsevier Ltd Vaccine development for antigenically variable pathogens has faltered because extreme genetic diversity precludes induction of broadly neutralizing antibodies (nAB) with classical vaccines. Here, using the most variable epitope of any known human pathogen (HVR1 of HCV), we describe a novel approach capable of eliciting broadly neutralizing antibodies targeting highly variable epitopes. Our proof-of-concept vaccine elicited pan-genotypic nAB against HCV variants differing from the immunogen sequences by more than 70% at the amino acid level. These findings suggest broadly nAB to highly variable pathogens can be elicited by vaccines designed to target physicochemically conserved residues within hypervariable epitopes

Role of HVR1 sequence similarity in the cross-genotypic neutralization of HCV

Despite available treatments, a prophylactic HCV vaccine is needed to achieve elimination targets. HCV vaccine development has faltered largely because the extreme diversity of the virus limits the protective breadth of vaccine elicited antibodies. It is believed that the principle neutralizing epitope in natural infection, HVR1, which is the most variable epitope in HCV, mediates humoral immune escape. So far, efforts to circumvent HVR1 interference in the induction and function of conserved targeting Ab have failed. Efforts to understand factors contributing to cross-neutralization of HVR1 variants have also been limited. Here, following mouse immunizations with two patient-derived HVR1 peptides, we observe cross-genotype neutralization of variants differing at 15/21 positions. Surprisingly, sequence similarity was not associated with cross-neutralization. It appeared neutralization sensitivity was an intrinsic feature of each variant, rather than emergent from the immunogen specific Ab response. These findings provide novel insight into HVR1-mediated immune evasion, with important implications for HCV vaccine design

Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B:Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial

INTRODUCTION:Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn.METHODS:Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA &lt;103IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria.RESULTS:Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (&gt;5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P &lt; 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal.DISCUSSION:Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log10IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.</p

Toronto HCC Risk Index::A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis

Background: Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. Aim: To assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk. Methods: A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system evaluated in an external cohort for validation. Results: Of 2,079 patients with cirrhosis and ≥6 months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p&lt;0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low (&lt;120 points) medium (120-240) and high (&gt;240) risk groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with PBC, HBV and HCV cirrhosis (n= 1,144) with similar predictive ability (Harrell’s c-statistic 0.77) in the validation and derivation cohorts. Conclusion: HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis

Progression of the FIB-4 index among patients with chronic HCV infection and early liver disease

Background and aims:Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease. Methods and results:Patients diagnosed with chronic HCV and FIB-4 &lt;3.25 from four international liver clinics were included in a retrospective cohort study. Follow-up ended at start of antiviral therapy resulting in sustained virological response, at time of liver transplantation or death. Primary outcome of advanced liver disease was defined as FIB-4 &gt;3.25 during follow-up. Survival analyses were used to assess time to FIB-4 &gt;3.25. In total, 4286 patients were followed for a median of 5.0 (IQR 1.7-9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39-55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4 &lt;1.45. Advanced liver disease developed in 821 patients. Overall, 10-year cumulative incidence of advanced disease was 32.1% (95% CI 29.9% to 34.3%). Patients who developed advanced disease showed an exponential FIB-4 increase. Among patients with a presumed date of HCV infection, cumulative incidence of advanced disease increased 7.7-fold from 20 to 40 years as opposed to the first 20 years after HCV infection. Conclusions:The rate of advanced liver disease is high among chronic HCV-infected patients with early disease at time of diagnosis, among whom liver disease progression accelerated over time. These results emphasise the need to overcome any limitations with respect to diagnosing and treating all patients with chronic HCV across the globe.</p