A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial.

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

Measuring quality of hepatitis B care in a remote Australian Aboriginal community: opportunities for improvement.

BACKGROUND: Chronic hepatitis B (CHB) infection remains a significant public health issue for Indigenous Australians, in particular for remote communities. AIM: To evaluate the spectrum of hepatitis B virus (HBV) care provided to a remote Aboriginal community. Measures studied included screening, seroprevalence, vaccination rates and efficacy, and HCC risk and surveillance adherence. METHODS: A retrospective audit of HBV care received by all permanent residents currently attending a remote Aboriginal Health service. This study was endorsed by both the local Aboriginal Health service and the Aboriginal Health Council of South Australia. RESULTS: A total of 208 patients attended the clinic, of whom 52% (109) were screened for HBV. Of these, 12% (13) had CHB and 20% (22) had evidence of past infection. Similarly, of the 208 attending patients, complete vaccination was documented in 48% (99). Of the 33 patients with post-vaccination serology, 24% (8) had subtherapeutic (<10 IU/mL) levels of HBsAb. Subtherapeutic HBsAb was independently associated with higher Charlson Comorbidity scores (odds ratio = 17.1; 95% confidence interval 1.2-243.3; P = 0.036). Definitive breakthrough infection was identified in 6% (2) patients. One HBsAg positive patient was identified as needing HCC surveillance, but had not undertaken HCC surveillance. CONCLUSION: Opportunities to improve the quality of CHB care through increased HBV vaccination, screening and adherence to HCC surveillance were identified. High rates of subtherapeutic vaccine responses and documented breakthrough infection raises concerns about the effectiveness of current CHB vaccines in this population.

Clinical factors leading to a change in management in chronic hepatitis B patients managed in a tertiary setting.

BACKGROUND: Newer antiviral agents for chronic hepatitis B (CHB) are highly effective, with minimal risks of complications and development of resistance. AIM: To identify the proportion of patients with CHB on treatment who will not require alteration of management and the clinical factors of those who will require closer monitoring. METHODS: Patients with CHB who were on entecavir and/or tenofovir between January 2011 and December 2016 were retrospectively studied. According to the initial treatment plan provided by the managing physician, any deviation in the interval of follow up, choice of investigations and alteration of medical therapy were considered a change in CHB management. We also evaluated the predictability of these changes, factors associated with higher frequency of change and the additional cost of managing stable patients with CHB in a tertiary setting. RESULTS: Of the patients, 75.7% (n = 87/115) did not have a change in CHB management; 85.6% of the changes in management were predictable based on liver function tests, hepatitis B virus DNA polymerase chain reaction levels and liver ultrasound. Interpreter use (OR (95% CI) = 2.41 (1.01-5.76)), liver cirrhosis (OR (95% CI) = 4.11 (1.44-11.75)) and immunosuppression (OR (95% CI) = 3.81 (1.2-12.06)) were associated risk factors. Overall, there was an incremental annual cost of AU$60 166 to manage patients who did not require alteration of their CHB management in our institution. CONCLUSION: The majority of stable CHB patients on highly potent antiviral treatment do not require alteration of management. While additional investigations are required, this study highlights the potential for a shared primary care approach in highly selected CHB patients.

The Chronic Liver Disease Nurse Role in Australia: Describing 10 Years of a New Role in Cirrhosis Management.

Cirrhosis of the liver is increasing, with growing patient numbers in hospital outpatient departments, as well as increasing admissions due to decompensated liver disease. Decompensated cirrhosis of the liver is a common and debilitating illness causing disability, readmissions to hospital, and decreased quality of life, and can lead to liver cancer. The advent of the chronic liver disease nurse (CLDN) position in our hospital in 2009 was the first role in Australia dedicated to providing care to patients with cirrhosis. The role incorporates the care of patients with stable compensated disease, case management of patients with complications of decompensated disease, and hepatocellular carcinoma coordination. After a pilot randomized controlled trial and almost 10 years of service, this article describes the role of the CLDN and presents key performance indicators that will assist other centers considering introducing the role or elements of it into their service.

Efficacy of High-Dose, Rapid, Hepatitis A and B Vaccination Schedules in Patients With Cirrhosis.

Patients with cirrhosis have increased morbidity from hepatitis A virus (HAV) and hepatitis B virus (HBV) infections, and vaccination against these infections is an important standard of care.1,2 However, vaccination in patients with cirrhosis is hindered by immune dysfunction and there is limited high-quality literature available. The aim of this work therefore was to compare immune responses of standard dose (SD) with high-dose accelerated (HDA) vaccination in cirrhotic patients.

High rates of indeterminate interferon-gamma release assays for the diagnosis of latent tuberculosis infection in liver transplantation candidates.

BACKGROUND AND AIMS: Screening for latent tuberculosis infection (LTBI) is recommended prior to solid organ transplantation. Interferon-gamma release assays (IGRAs) are the most widely used test for LTBI screening; however, assessment of IGRA performance in patients with end-stage liver disease is limited. The purpose of this study was to evaluate the prevalence and predictors of indeterminate (INDT) IGRA results in liver transplantation candidates. METHODS: Between March 2011 and May 2018, we retrospectively analyzed 155 patients undergoing liver transplantation assessment, who underwent IGRA testing (Quantiferon-TB Gold, QFT-G) to exclude LTBI. Characteristics of patients, including age, gender, etiology of liver disease, MELD score, and absolute lymphocyte counts, were compared by QFT-G result (determinate vs INDT). RESULTS: Of the 155 patients screened, the rate of positive, negative, and INDT results were 5.2%, 69.8%, and 25%, respectively. The only variable independently associated with an indeterminate test on multivariate analysis was MELD score (odds ratio = 1.07, 95% CI = 1.01-1.14 per unit increase; P = 0.014). In 95% of INDT tests, both TB antigen tube and the positive control tube were negative and repeat testing gave the same indeterminate result, suggestive of anergy rather than laboratory error. CONCLUSIONS: Our study suggests a high rate of INDT IGRA results during screening of liver transplant candidates for LTBI, associated with severity of liver disease and anergy. Because of the high rate of INDT QFT-G testing in this setting, individualized risk assessment is required including a thorough assessment of clinical risk factors and knowledge of local TB prevalence.

The Interferon-induced Transmembrane Proteins, IFITM1, IFITM2, and IFITM3 Inhibit Hepatitis C Virus Entry.

The interferon-induced transmembrane (IFITM) family of proteins have recently been identified as important host effector molecules of the type I interferon response against viruses. IFITM1 has been identified as a potent antiviral effector against hepatitis C virus (HCV), whereas the related family members IFITM2 and IFITM3 have been described to have antiviral effects against a broad range of RNA viruses. Here, we demonstrate that IFITM2 and IFITM3 play an integral role in the interferon response against HCV and act at the level of late entry stages of HCV infection. We have established that in hepatocytes, IFITM2 and IFITM3 localize to the late and early endosomes, respectively, as well as the lysosome. Furthermore, we have demonstrated that S-palmitoylation of all three IFITM proteins is essential for anti-HCV activity, whereas the conserved tyrosine residue in the N-terminal domain of IFITM2 and IFITM3 plays a significant role in protein localization. However, this tyrosine was found to be dispensable for anti-HCV activity, with mutation of the tyrosine resulting in an IFITM1-like phenotype with the retention of anti-HCV activity and co-localization of IFITM2 and IFITM3 with CD81. In conclusion, we propose that the IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation and demonstrate that the actions of the IFITM proteins are indeed virus and cell-type specific.

Signal transducer and activator of transcription 3 is a proviral host factor for hepatitis C virus.

UNLABELLED: Host factors play an important role in all facets of the hepatitis C virus (HCV) life cycle and one such host factor is signal transducer and activator of transcription 3 (STAT3). The HCV core protein has been shown to directly interact with and activate STAT3, while oxidative stress generated during HCV replication in a replicon-based model also induced STAT3 activation. However, despite these findings the precise role of STAT3 in the HCV life cycle remains unknown. We have established that STAT3 is actively phosphorylated in the presence of replicating HCV. Furthermore, expression of a constitutively active form of STAT3 leads to marked increases in HCV replication, whereas, conversely, chemical inhibition and small interfering RNA (siRNA) knockdown of STAT3 leads to significant decreases in HCV RNA levels. This strongly implicates STAT3 as a proviral host factor. As STAT3 is a transcription factor, up-regulation of a distinct set of STAT3-dependent genes may create an environment that is favorable for HCV replication. However, STAT3 has recently been demonstrated to positively regulate microtubule (MT) dynamics, by way of a direct sequestration of the MT depolymerizing protein Stathmin 1 (STMN1), and we provide evidence that STAT3 may exert its effect on the HCV life cycle by way of positive regulation of MT dynamics. CONCLUSION: We have demonstrated that STAT3 plays a role in the life cycle of HCV and have clarified the role of STAT3 as a proviral host factor.

Integrating smart phone applications in the management of cirrhotic patients: A scoping review.

Background and Aim: Chronic liver disease and cirrhosis is a significant cause of healthcare utilization and patient morbidity and mortality worldwide. Smartphone applications have high uptake in most communities and therefore have great potential to provide remote support solutions to this patient population. The aim of this scoping review was therefore to provide a comprehensive overview using narrative synthesis on the use of smartphone-application-based digital interventions in cirrhotic populations. Materials and Methods: PRISMA guidelines were followed, with two independent researchers identifying 10 relevant studies. Patients studied were predominantly those with decompensated cirrhosis, and hepatic encephalopathy was the most common complication studied. Results: Smartphones were the most common platform used, but training periods, prior to commencement of the study, were rarely offered. Patient engagement rates with the technology were reported only in three studies, but all reported high (>50%) rates of engagement. Only one study examined the clinical effects of their digital intervention, with a 38% reduction in readmission rate reported. Conclusion: Overall, the use of smartphone apps in cirrhosis is in an early phase of development and evaluation but preliminary studies suggest significant potential as an adjunct to routine medical care. Further high-quality studies of well-designed digital interventions are needed to advance this promising early experience.

The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A.

UNLABELLED: The interferon-stimulated gene, viperin, has been shown to have antiviral activity against hepatitis C virus (HCV) in the context of the HCV replicon, although the molecular mechanisms responsible are not well understood. Here, we demonstrate that viperin plays an integral part in the ability of interferon to limit the replication of cell-culture-derived HCV (JFH-1) that accurately reflects the complete viral life cycle. Using confocal microscopy and fluorescence resonance energy transfer (FRET) analysis, we demonstrate that viperin localizes and interacts with HCV nonstructural protein 5A (NS5A) at the lipid-droplet (LD) interface. In addition, viperin also associates with NS5A and the proviral cellular factor, human vesicle-associated membrane protein-associated protein subtype A (VAP-A), at the HCV replication complex. The ability of viperin to limit HCV replication was dependent on residues within the C-terminus, as well as an N-terminal amphipathic helix. Removal of the amphipathic helix-redirected viperin from the cytosolic face of the endoplasmic reticulum and the LD to a homogenous cytoplasmic distribution, coinciding with a loss of antiviral effect. C-terminal viperin mutants still localized to the LD interface and replication complexes, but did not interact with NS5A proteins, as determined by FRET analysis. CONCLUSION: In conclusion, we propose that viperin interacts with NS5A and the host factor, VAP-A, to limit HCV replication at the replication complex. This highlights the complexity of the host control of viral replication by interferon-stimulated gene expression.

High rates of treatment stage migration for early hepatocellular carcinoma and association with adverse outcomes: An Australian multicenter study.

Background and Aim: The rate of contraindications to percutaneous ablation (PA) for inoperable early hepatocellular carcinoma (HCC) and subsequent outcomes is not well described. We investigated the prevalence and outcomes of inoperable early HCC patients with contraindications to PA, resulting in treatment stage migration (TSM). Methods: Barcelona Clinic Liver Cancer (BCLC) 0/A patients diagnosed between September 2013 and September 2019 across five hospitals were identified. Primary endpoint was proportion of BCLC 0/A HCCs with contraindications to PA. Secondary endpoints included overall survival (OS), local tumor control (LTC), and recurrence-free survival (RFS). The causal effects of PA versus TSM were assessed using a potential outcome means (POM) framework in which the average treatment effects (ATEs) of PA were estimated after accounting for potential selection bias and confounding. Results: Two hundred twenty patients with inoperable BCLC 0/A HCC were identified. One hundred twenty-two patients (55.5%) had contraindications to PA and received TSM therapy, 98 patients (44.5%) received PA. The main contraindication to PA was difficult tumor location (51%). Patients who received TSM therapy had lower median OS (2.4 vs 5.3 years), LTC (1.0 vs 4.8 years), and RFS (0.8 vs 2.9 years); P < 0.001, respectively, compared with PA. The ATE for PA versus TSM yielded an additional 1.11 years (P = 0.019), 2.45 years (P < 0.001), and 1.64 years (P < 0.001) for OS, LTC, and RFS, respectively. Three-year LTC after PA was suboptimal (65%). Conclusion: Our study highlights high rates of contraindication to PA in early HCCs, resulting in TSM and poorer outcomes. The LTC rate for PA appears suboptimal despite being considered as curative therapy. Both findings support the exploration of improved treatment options for early HCCs.

Association of physiological reserve measures with adverse outcomes following liver transplantation.

BACKGROUND AND AIM: The comparative utility of physiological reserve measures in predicting important clinical outcomes following liver transplantation (LT) requires further study. The aim of this work was therefore to compare the utility of physiological reserve measures in predicting early adverse clinical outcomes post-LT. METHODS: A single-center, retrospective cohort study of LT patients consecutively recruited between 1 January 2015, and 31 August 2020. Outcomes measured were sepsis and death within 12 months of LT, hospital length of stay (LOS), and intensive care LOS. Physiological reserve measures were handgrip strength, mid-arm muscle circumference, and cardiopulmonary exercise testing (CPET) measures. Analysis was performed using univariate and multivariate logistic regression for sepsis and death, and univariate and multivariate Cox regression for hospital and intensive care LOS. RESULTS: Data were obtained for 109 subjects. Patients were predominantly (64%) male with a median (interquartile range [IQR]) age of 57 (49-63) and median (IQR) Model for End-Stage Liver Disease score of 16 (11-21). In multivariate analysis, the odds of sepsis were lower in patients in the highest versus lowest tertile (odds ratio = 0.004; 95% confidence interval [CI] 0.00-0.13; P = 0.002). Hospital LOS was linearly associated with handgrip strength (hazard ratio [HR] = 1.03; 95% CI 1.00-1.06; P = 0.03) in multivariate analysis. Intensive care LOS was associated with peak VO2 (HR 1.83; 95% CI 1.06-3.16; P = 0.03) and VE/VCO2 slope (HR 0.71; 95% CI 0.58-0.88; P = 0.002) in multivariate analysis. CONCLUSION: Handgrip strength and CPET both identify candidates at high risk of adverse outcomes after LT.

Outcomes of transjugular intrahepatic portosystemic shunt procedures: a 10-year experience.

INTRODUCTION: Transjugular intrahepatic portosystemic shunt (TIPSS) is an effective modality in reducing portal pressure, and its current main indications are for the management of recurrent ascites and variceal bleeding. The demand and indications for TIPSS are growing. However, it is a complicated and technically demanding procedure with poorer outcomes associated with low volume centres. The aim of this study was, therefore, to review the outcomes of TIPSS at a 'low volume' single centre. Outcomes assessed included indications, safety, efficacy and survival. METHODS: A retrospective study was undertaken of all patients who underwent a TIPSS procedure over 10 years at tertiary referral centre for complex liver disease and transplantation. Kaplan-Meier method was used to calculate actuarial survival and log-rank analysis was used to determine significant differences in survival. RESULTS: Thirty-eight patients underwent the TIPSS procedure between January 2008 and December 2018. Technical, haemodynamic and clinical success were 95%, 92% and 92% respectively. Cumulative survival at one month, one year and five years were 86.8%, 72% and 44.7% respectively. Results achieved standards published in practice parameters to evaluate TIPSS safety and efficacy. CONCLUSION: At a low volume centre, TIPSS usage was associated with high rates of technical, haemodynamic (HPVG reduction) and clinical success. Low volume should not be a contraindication to providing a TIPSS service; however, auditing outcomes and understanding specific institutional factors that influence quality are important requirements for low volume centres.

Hepatocellular carcinoma amongst Aboriginal and Torres Strait Islander peoples of Australia.

BACKGROUND: Liver disease and hepatocellular carcinoma (HCC) are important contributors to the mortality gap between Indigenous and non-Indigenous Australians. However, there is a lack of population based high quality data assessing the differences in HCC epidemiology and outcomes according to Indigenous status. The aim of this study was therefore to perform a large epidemiological study of HCC investigating differences between Indigenous and non-Indigenous Australians with HCC. METHODS: Study design was a retrospective cohort study. Data linkage methodology was used to link data from cancer registries with hospital separation summaries across three Australian jurisdictions during 2000-2017. Cumulative survival (Kaplan-Meier) and the differences in survival (Multivariable Cox-regression) by Indigenous status were assessed. FINDINGS: A total of 229 Indigenous and 3587 non-Indigenous HCC cases were included in the analyses. Significant epidemiological differences identified for Indigenous HCC cases included younger age at onset, higher proportion of females, higher rurality, lower socioeconomic status, and higher comorbidity burden (all p < 0.001). The distribution of cofactors was also significantly different for Indigenous Australians including higher prevalence of alcohol misuse, hepatitis B, and diabetes and more frequent presence of multiple HCC cofactors (all p < 0.001). Indigenous Australians received curative HCC therapies less frequently (6.6% vs. 14.5%, p < 0.001) and had poorer 5-year survival (10.0% vs. 17.3%, p < 0.001; unadjusted hazard ratio (HR) =1.42 96%CI 1.21-1.65) compared to non-Indigenous Australians. The strength of the association between indigenous status and survival was weaker and statistically non-significant after adjusting for rurality, comorbidity burden and lack of curative therapy (adjusted-HR=1.20 95%CI 0.97-1.47). INTERPRETATION: Such data provide a call to action to help design and implement health literacy, liver management and HCC surveillance programs for Indigenous people to help close the liver cancer mortality gap.

Stereotactic body radiation therapy for early hepatocellular carcinoma: a retrospective analysis of the South Australian experience.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumours unsuitable for established curative treatment such as ablation or surgery. The aim of the study is to evaluate the efficacy and safety of SBRT in the treatment of small hepatocellular carcinoma (HCC) in South Australia. METHODS: From 2014 to 2018, 13 HCC patients were treated with SBRT. Eligibility criteria for SBRT included: unsuitable for standard curative therapies (resection or percutaneous ablation), lack of complete response to prior transarterial chemoembolization, Child-Pugh classification ≤B7, tumours ≤5 cm and minimum of up to 6 months follow-up post-SBRT. The prescribed radiation dose was determined by liver function with doses ranging from 40 to 45 Gy in three or five fractions. Records for all patients were reviewed, and treatment response was scored according to the modified response evaluation criteria in solid tumours. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up time was 22.7 months, and the median tumour size was 40 mm. The 1 year local control was 92.3%, recurrence-free survival was 67.7% and overall survival was 86.4% at end of study. Three patients underwent liver transplant. No grade ≥3 non-haematological toxicities were observed. One patient experienced acute grade ≥3 haematological toxicity. CONCLUSION: SBRT is a safe, effective and non-invasive alternative treatment option for patients with small HCCs, unsuitable for standard, evidence-based therapies and lacking complete response to transarterial chemoembolization. Randomized controlled trials are required to further investigate the role of SBRT in HCC.

Generation of a chimeric hepatitis C replicon encoding a genotype-6a NS3 protease and assessment of boceprevir (SCH503034) sensitivity and drug-associated mutations.

BACKGROUND: Genotype (gt)6 HCV is common amongst HCV-positive populations of the Asia-Pacific region but cell culture models for this gt have only recently been developed. Boceprevir (SCH503034) is a clinically available inhibitor of the HCV NS3 protein. We investigated the efficacy of boceprevir for inhibiting replication of a chimeric gt1b replicon encoding a gt6a NS3 protease and defined the development of mutations in the protease when boceprevir treatment was applied. METHODS: We constructed a chimeric gt1b subgenomic replicon encoding a gt6 NS3 protease (NS3p) sequence (gt6NS3p_gt1b). The boceprevir EC50 value against replication of this replicon was determined using quantitative reverse transcriptase PCR. Next-generation sequencing was used to identify nucleotide changes associated with boceprevir resistance. The replication capacities of chimeric replicons containing mutations associated with boceprevir resistance were determined by colony formation efficiency assays. RESULTS: The boceprevir EC50 value for the gt6NS3p_gt1b replicon was 535 ±79 nM. Boceprevir-resistant gt6NS3p_gt1b replicon cell lines could be selected and they demonstrated drug-associated amino acid changes that have previously been reported in other HCV gts. Interestingly, no mutations were observed at A156, a position defined for boceprevir resistance in gt1 NS3p, while mutation at N122, which is rarely reported in boceprevir-resistant gt1 proteases, was frequently observed. Re-introduction of these mutations into the chimeric replicon altered their replication capacity, ranging from complete abolishment of replication (A156T) to increasing replication capacity (V36A, N122S). This report provides the first characterization of gt6 HCV resistance to boceprevir. CONCLUSIONS: A chimeric HCV replicon encoding gt6 NS3 protease is sensitive to boceprevir and develops drug-resistant mutations at amino acid sites previously reported for other gts. Mutation at N122 also appears to be associated with boceprevir resistance in the gt6 NS3 protease.

Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin.

The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co-localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV-2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein.