Hepatitis C Virus Therapy Research Articles

Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment.

Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.

Improvement of patient-reported outcomes in patients achieving sustained virologic response with direct-acting antivirals for hepatitis C virus infection.

Patient-reported outcome (PRO) in patients with chronic hepatitis C virus (HCV) infection (CHC) after successful direct-acting antiviral (DAA) therapy remains elusive. The study aimed to investigate the impact of DAA therapy on health-related quality of life (HRQoL). We also assess the associated factors predictive of HRQoL change after sustained virologic response (SVR) to HCV therapy. CHC patients receiving DAA therapy were prospectively recruited. They completed paired HRQoL assessments which included Short-Form-36 (SF-36), Pittsburgh Sleep Quality Index (PSQI) score, Taiwanese Depression Questionnaire score, and State Trait Anxiety Inventory (STAI) score before treatment and at Week 12 off-treatment. Clinical data and characteristics were compared in a paired manner. A total of 158 patients achieved SVR (SVR rate: 96.6%) were enrolled into the final analysis. Improvement of depression, anxiety, digestive symptoms, and SF-36 items of vitality, body pain, physical functioning, emotional functioning, social functioning, and mental health were demonstrated among SVR patients. Sleep quality, or other SF-36 items were not significantly changed after the treatment. Multivariate analysis revealed that improvement of sleep quality, depression, and anxiety were associated with better HRQoL. SVR to HCV therapy by DAA significantly improved PROs including HRQoL.

Contemporary Changes in Etiology for Hepatocellular Carcinoma in Liver Transplantation

The major risk factor for developing hepatocellular carcinoma (HCC) is chronic liver disease, with hepatitis C virus (HCV) and alcohol-related liver disease (ARLD) predominating historically in the United States.1 However, with the recent availability of safe and effective direct-acting antiviral (DAA) therapy for HCV, and the continuing rise in nonalcoholic steatohepatitis (NASH), the relative etiology of HCC could further evolve.1–4 In 2016, ARLD and NASH surpassed HCV as the leading indication for liver transplant (LT) in patients without HCC; similar trends may be expected for HCC LT downstream.

Fibrosis regression following hepatitis C antiviral therapy

Hepatitis C virus (HCV) infection is one of the most common causes of liver pathology. It is a major etiological factor of continuous liver injury by triggering an uncontrolled inflammatory response, causing liver fibrosis and cirrhosis. Liver fibrosis is a dynamic process that can be reversible upon timely cessation of the injurious agent, which in cases of HCV is represented by the sustained virological response (SVR) following antiviral therapies. Direct-acting antiviral therapy has recently revolutionized HCV therapy and minimized complications. Liver fibrosis can be assessed with variable invasive and non-invasive methods, with certain limitations. Despite the broad validation of the diagnostic and prognostic value of non-invasive modalities of assessment of liver fibrosis in patients with HCV, the proper interpretation of liver stiffness measurement in patients after SVR remains unclear. It is also still a debate whether this regression is caused by the resolution of liver injury following treatment of HCV, rather than true fibrosis regression. Regression of liver fibrosis can possess a positive impact on patient's quality of life reducing the incidence of complications. However, fibrosis regression does not abolish the risk of developing hepatocellular carcinoma, which mandates regular screening of patients with advanced fibrosis.

Elevated liver enzymes predict morbidity and mortality despite antiviral cure in patients with chronic hepatitis C: Data from the German Hepatitis C-Registry.

While direct‐acting antivirals (DAAs) cure chronic hepatitis C virus (HCV) infection in almost all patients, some patients remain at risk of liver disease despite HCV cure. In order to identify risk factors indicating liver‐related morbidity and death after viral cure, we included 6982 patients from the national multicenter real‐world German Hepatitis C Registry with regular follow‐up visits for up to 7 years after DAA therapy. Definitions for normal liver function tests (in women/men) were alanine aminotransferase (ALT; ≤35/≤50 U/L), ALT according to American Association for the Study of Liver Diseases (AASLD; ≤19/≤30 U/L), and gamma‐glutamyltransferase (GGT; ≤40/≤60 U/L). In our cohort, 97.4% of patients achieved sustained virologic response (SVR). At 24 weeks after SVR (SVR24), elevated ALT occurred in 657/6982 (9.4%), elevated ALT (AASLD) in 2609/6982 (37.4%), and elevated GGT in 1777/6982 (25.5%) patients. Risk factors for increased ALT at SVR24 were obesity, alcohol, cirrhosis, elevated baseline ALT, and non‐SVR. Increased GGT at SVR24 was significantly (p < 0.05) and independently associated with male sex (odds ratio [OR], 2.12), higher body mass index (OR, 1.04), age >50 years (OR, 1.60), liver cirrhosis (OR, 3.97), alcohol consumption (OR, 2.99), diabetes (OR, 1.63), non‐SVR (OR, 8.00), and elevated GGT at baseline (OR, 17.12). In multivariate regression analysis, elevated GGT at SVR24, particularly in combination with cirrhosis, was the best predictor for hepatic decompensation, hepatocellular carcinoma development, and death, followed by elevated ALT (AASLD) and standard ALT, which predicted hepatic decompensation. Despite successful HCV therapy, elevated GGT at SVR24 and to a lesser extent ALT are predictive of the future clinical outcome and linked with liver‐associated comorbidities. This may highlight the relevance of nonalcoholic fatty liver disease, diabetes mellitus, alcohol, and cirrhosis for the clinical outcome in a vulnerable population, even after HCV cure.

Risk Factors for Treatment Failure with Oral Antivirals in HCV

Introduction: Chronic hepatitis C virus (HCV) infection is one of the major cause of cirrhosis of liver and leads to significant morbidity and mortality. In past, HCV therapy was limited to subcutaneous peg interferon plus oral ribavirin, a regimen that was generally poorly tolerated and provided low efficacy, with cure rates below 40% for HCV genotypes 1 and 4, and below 75% for HCV genotypes 2 or 3. The availability of oral direct-acting antiviral (DAA) as treatment for chronic hepatitis C has revolutionized the field. Although current HCV therapies rarely fail to achieve viral eradication, a subset of patients experience treatment failure. Aim: To study the risk factors associated with treatment failure with oral antiviral drugs in patients of Chronic hepatitis C. Materials &amp; Methods: It was a retrorospective study done at Medical Gastroenterology Department, PGIMS, Rohtak in which six years data i.e.from 01.01.2015 to 31.12.2020, pertainining to Eighty Six (86) chronic hepatitis C patients who had treatment failure i.e. SVR failure on oral antiviral drugs was analyzed. Observations: Out of the total 86 patients, there was clear cut male predominance i.e. 54 (62.79 %) with rural background (villages) i.e.73 (84.88%). The age distribution in these 86 patients varied between 10-80 yrs of age and characterstically peak was seen in 31-40 yrs age group i.e.25 patients (29.06 %). The majority of patients had high baseline HCV viral load (&gt; 4 lakhs I.U. /ml) i.e. 52 patients (60.46%). Out of total 86 patients, , 50 patients (58.13%) were cirrhotic, 34 patients (39.53 %) were smokers, 33 patients (38.37%) were alcoholic, 26 patients (30.23 %) had past history of surgical intervention, 9 patients (10.46 %) were diabetic, 9 patients (10.46 %) had got tattoo, 8 patients (9.30%) had history of previous blood transfusion and 13 patients (15.11%) gave history of use of alternative medications. Results: The direct risk factors associated with development of failed SVR in HCV patients are high baseline HCV RNA viral load, cirrhosis, rural background and indirect risk factors are smoking, alcohol and Diabetes Mellitus but large scale studies in future are required to confirm the same.

Avoidance of drug interactions with hepatitis C treatment: Evaluation of pharmacist interventions in the specialty setting

ObjectivesDirect-acting antiviral (DAA) therapy is currently recommended for most patients chronically infected with the hepatitis C virus (HCV) by the American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines. DAAs have significant drug interaction potential, which can lead to treatment failure and adverse drug events. The primary goal of this study is to report the number and nature of interventions made by pharmacists regarding drug interactions in patients using DAA therapy and to estimate the cost avoidance of averting potential DAA treatment failures. MethodsThe patients in this cohort were identified through the pharmacy’s electronic medical record if they were at least 18 years old while having filled a prescription for a DAA between 6/1/2019 and 06/01/2020. Data for this study were collected retrospectively using a report generated by the pharmacy electronic medical record and through manual chart review. Calculations for cost avoidance associated with prevention of DAA treatment failures are estimations based on the current average wholesale price (AWP) and wholesale acquisition cost (WAC) pricing. ResultsA total of 808 patients were identified as filling a prescription for HCV treatment during the measurement period. Average patient age was 49.8 years, and 60.5% of patients were male. A total of 267 patients (33%) were identified as having at least one drug-drug or drug-disease interaction. Of the 304 potential interactions identified, 132 drug interactions (43.9%) could have led to treatment failure and 172 (56%) could have resulted in adverse events. The estimated cost avoidance for interventions made by clinical pharmacists to avert treatment failures (132 regimens) was $387,968 and $323,306 using AWP and WAC pricing, respectively. ConclusionPharmacists in the specialty pharmacy setting are essential for the evaluation of potential drug and disease state interactions with HCV therapies. These interventions potentially averted treatment failures and adverse drug events.

Antiviral Treatment for Hepatitis C Is Associated With a Reduced Risk of Periprosthetic Joint Infection: A Meta-Analysis of Observational Studies

BackgroundRecently, preoperative antiviral therapies for hepatitis C virus (HCV) have become available for total joint arthroplasty (TJA) patients. The objective of this meta-analysis is to investigate the impact of anti-HCV treatment on the incidence of postoperative complications after primary TJAs. MethodsWe searched PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library databases for relevant studies from inception to March 5, 2022. The pooled odds ratios with 95% CI of the risk of postoperative complications were calculated using the random effects model. Subgroup analyses were conducted on the basis of surgery type, antiviral regimes, and duration of follow-up. ResultsEight retrospective cohort studies fulfilled the inclusion and exclusion criteria, involving 9,703 subjects. Overall, antiviral therapy for HCV was associated with a reduced risk of all-type complications and surgical complications. Moreover, we found that HCV-infected patients without treatment had substantially higher rates of periprosthetic joint infection at any surgery type and follow-up time point. There was a tendency for favoring a lower pooled revision/reoperation rate and mechanical complication rate in treated patients compared with untreated patients, but the differences failed to reach statistical significance. When limiting analysis to patients receiving preoperative direct acting antiviral-based therapy, untreated patients still had a higher surgical complication rate and joint infection rate. ConclusionThis meta-analysis demonstrated that antiviral therapy for HCV appears to be associated with a reduced risk of surgical complications in TJA patients, particularly periprosthetic joint infection. Thus, direct-acting antiviral therapy could be recommended for patients diagnosed with HCV.

Pursuing Elimination of HepatitisC in Egypt: Cost-Effectiveness and Economic Evaluation of a Country-Wide Program.

IntroductionHepatitis C virus (HCV) is a global public health crisis. Egypt presents the highest HCV global prevalence. Recently, three different HCV screening/testing/therapy programs were implemented: In 2014 (wave 1), major decisions on HCV therapy were enacted, accompanied by a 99% discount for the HCV therapy sofosbuvir. In 2016 (wave 2), a first testing program was launched to identify patients for free treatment. In 2018 (wave 3), population-wide screening was conducted using a WHO-prequalified finger prick rapid diagnostic test (RDT) to identify/treat all Egyptians with HCV. The financial advantages of HCV screening programs (wave 1–3 results) were estimated vs a baseline period of limited Egyptian HCV testing/therapeutic intervention (2008–2014).MethodsUsing published evidence and model-based estimates from real-world data, we evaluated the direct costs of the different HCV programs, accompanied by a conservative simulation of major HCV health consequences (i.e., liver-related deaths/life years lost) and related indirect costs. Total economic consequences of each HCV program were compared to each other and baseline from a societal perspective. Future costs and health effects were discounted by 3.5% per year.ResultsDiscounted total costs (in US dollars) were $1,057 billion (baseline), $913 million (wave 1), $457 million (wave 2), and $396 million (wave 3). Discounted HCV-related life years lost were 418,000 (baseline), 377,000 (wave 1), 142,000 (wave 2), and 62,000 (wave 3). With each successive Egyptian HCV screening/testing/therapy wave, total costs and HCV-related mortality were reduced.ConclusionUse of the community-applied, WHO-prequalified RDT was the most dominant approach to cost-effectiveness. These results provide rationale for worldwide scalability of similar HCV elimination programs.

The curing regimens of HCV: A SWOT analysis.

The development of direct-acting antivirals (DAA) has revolutionized the treatment of chronic hepatitis C, enabling cure of hepatitis C virus (HCV) infection in more than 95% of cases. There are essentially no contraindications, so almost any patient can now be successfully treated. The result is the prevention or amelioration of cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Consequently, the 2020 Nobel Prize in Medicine and Physiology was awarded for the discovery of HCV. Due to the high efficacy of therapy, even global HCV elimination is conceivable even without a vaccine. Here, we would like to venture a SWOT analysis of current HCV therapies aimed at HCV elimination.

Emergency department versus community screening on hepatitis C follow-up care

ObjectivesEmergency department (ED) hepatitis C virus (HCV) screening programs are proliferating, and it is unknown whether EDs are more effective than traditional community screening at promoting HCV follow-up care. The objective of this study was to investigate whether patients screened HCV seropositive (HCV+) in the ED are linked to care and retained in treatment more successfully than patients screened HCV+ in the community. MethodsA retrospective cohort study was performed including patients screened HCV+ at twelve screening facilities in New Orleans, LA from March 1, 2015 to July 31, 2017. Treatment outcomes, including retention and time to follow-up care, were assessed using the HCV continuum of care model. ResultsED patients (n = 3008) were significantly more likely to achieve RNA confirmation (aRR = 1.91, 95% CI = 1.54–2.37), initiate HCV therapy (aRR = 2.23 [1.76–2.83]), complete HCV therapy (aRR = 1.77 [1.40–2.24]), and achieve HCV functional cure (aRR = 2.80 [1.09–7.23]) compared to community-screened patients (n = 322). ED screening was associated with decreased likelihood of fibrosis staging (aRR = 0.65 [0.51–0.82]) and no difference in linkage to specialty care (aRR = 1.03 [0.69–1.53]). In time to follow up, RNA confirmation occurred at faster rates in the ED (aHR = 2.26 [1.86–2.72]), although these patients completed fibrosis staging at slower rates (aHR = 0.49 [0.38–0.63]) than community patients. ConclusionsCompared to community screening, HCV screening in the ED was associated with higher rates of disease confirmation, treatment initiation/completion, and cure. Our findings provide new evidence that EDs may be the most effective setting to screen patients for HCV to promote follow-up care.

In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models.

Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins. These models successfully predicted a total of 46 statin DDIs, including above DAA drugs and their fix-dose combination regimens. Predicted plasma area under curve ratio (AUCR) with and without perpetrator drugs was within ~ 2-fold of observed values. In contrast, simplified static R-value model resulted in increased false negative and false positive predictions when different prediction cut-off values were applied. Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.

Formal Hepatitis C Education Increases Willingness to Receive Therapy in an On-site Shelter-Based HCV Model of Care in Persons Experiencing Homelessness.

BackgroundThe objective of this study was to evaluate the effectiveness of formal hepatitis C virus (HCV) education on engagement in therapy in persons experiencing homelessness in an on-site shelter-based model of care. As policies to eliminate Medicaid access restrictions to HCV treatment are expanded, patient education is paramount to achieving HCV elimination targets in difficult-to-engage populations including persons experiencing homelessness.MethodsThis prospective study was conducted at 4 shelters in San Francisco and Minneapolis from August 2018 to January 2021. Of the 162 HCV Ab–positive participants, 150 participated in a 30-minute HCV education session. Posteducation changes in knowledge, beliefs, barriers to care, and willingness to accept therapy scores were assessed.ResultsFollowing education, knowledge scores (mean change, 4.4 ± 4.4; P < .001) and willingness to accept therapy (70% to 86%; P = .0002) increased. Perceived barriers to HCV care decreased (mean change, –0.8 ± 5.2; P = .001). Higher baseline knowledge was associated with lesser gain in knowledge following education (coef., –0.7; P < .001). Posteducation knowledge (odds ratio, 1.2; P = .008) was associated with willingness to accept therapy.ConclusionsAn HCV educational intervention successfully increased willingness to engage in HCV therapy in persons experiencing homelessness in an on-site shelter-based HCV model of care.

Incidence and Risk Factors of Reinfection with HCV after Treatment in People Living with HIV.

Infection with hepatitis C virus (HCV) does not induce protective immunity, and re-exposure to HCV can reinfect the population engaging in high-risk behavior. An increasing incidence of acute hepatitis C infection in people living with HIV (PLWH) has been described in recent years. This retrospective cohort study was conducted in PLWH who completed HCV therapy between June 2009 and June 2020 at an HIV care hospital, to analyze their basic characteristics and risky behavior. Of 2419 patients, 639 were diagnosed with HCV infection and 516 completed the HCV therapy with a sustained virologic response. In total, 59 patients (11.4%) were reinfected with acute hepatitis C, and the median time to reinfection was 85.3 weeks (IQR: 57–150). The incidence of reinfection was 6.7 cases/100 person-years. The factors associated with reinfection were being male (AHR, 8.02; 95% CI 1.08–59.49), DAA (direct-acting antiviral) treatment (AHR, 2.23; 95% CI 1.04–4.79), liver cirrhosis (AHR, 3.94; 95% CI 1.09–14.22), heroin dependency (AHR: 7.41; 95% CI 3.37–14.3), and HIV viral loads <50 copies/mL at the follow-up (AHR: 0.47, 95% CI 0.24–0.93) in the subgroup of people who inject drugs (PWID). Amphetamine abuse (AHR: 20.17; 95% CI 2.36–172.52) was the dominant factor in the subgroup of men who have sex with men (MSM). Our study suggests that education and behavioral interventions are needed in this population to prevent reinfection.

Nurse practitioners as primary care site champions for the screening and treatment of hepatitis C virus.

Primary care providers are often the first point of contact for hepatitis C virus (HCV) care, yet treatment initiation in primary care continues to be low. Nurse practitioners (NPs) are autonomous providers who, in Ontario, currently prescribe HCV therapy; however, methods to engage primary care NPs in HCV care have not occurred. To assess the feasibility of a systematic approach to train and support NPs in HCV testing, care, and treatment. Nurse practitioners from Canada's largest family health team (FHT) were recruited. Nurse practitioners received six hours of training and develop approaches to screen and treat at FHT sites. Treatment algorithms were given, and the number and types of inquiries from NPs were recorded. Over 1 year, 9 NPs screened 1,026 patients; 87.4% were screened based on the identification of a risk factor. A mail-out approach for birth cohort screening occurred at a single site, resulting in rapid uptake in screening. Antibody prevalence was 1.66%, with 76.5% RNA positivity. All RNA-positive treatment-eligible individuals were treated by an NP and completed treatment. Thirty-eight consults occurred over 1 year, the majority related to HCV or liver disease staging. Formalized initiatives to engage and educate NPs lead to innovative strategies to test for HCV. Nurse practitioners can safely and effectively treat HCV in primary care with minimal support. This work could be extrapolated to NPs in other primary care settings. Implementing formalized strategies has the potential to create NP leaders in the treatment and elimination of HCV in Ontario, Canada, and globally.

Risk of hepatocellular carcinoma after hepatitis C virus cure.

Hepatitis C virus (HCV) is a significant cause of hepatocellular carcinoma (HCC). The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95% cure rate. Successful treatment of chronic hepatitis C greatly reduces the risk of HCC. A proportion of patients, especially those with pre-existing cirrhosis, remain at risk for HCC despite sustained virologic response (SVR). Diabetes mellitus, hepatic steatosis, alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure. Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis. More recently, various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR. These models still need to be validated and standardized prior to applying to routine clinical care.

Motives and risk perceptions of participants in a phase 1 trial for Hepatitis C Virus investigational therapy in pregnancy

Limited research has been done among pregnant people participating in investigational drug trials. To enhance the ethical understanding of pregnant people’s perspectives on research participation, we sought to describe motives and risk perceptions of participants in a phase 1 trial of ledipasvir/sofosbuvir (LDV/SOF) treatment for chronic Hepatitis C virus (HCV) during pregnancy. Pregnant people with chronic HCV infection enrolled in an open-label, phase 1 study of LDV/SOF participated in semi-structured, in-depth interviews to explore their reasons for participation and experiences within the study. Pregnant people took 12 weeks of LDV/SOF and were interviewed at enrollment and at the end of study. We recorded the interviews, transcribed them verbatim, coded them using NVivo software, and performed inductive thematic analysis. Nine women completed the study yielding 18 interview transcripts. We identified two themes regarding motives and one regarding risk perception. Motives—(1) Women conceptualized study participation as part of the caregiving role they associate with motherhood; participating was viewed as an act of caregiving for their infants, their families, themselves, and other pregnant women with chronic HCV. (2) Women also noted that they faced multiple barriers to treatment prior to pregnancy that created a desire to receive therapy through trial participation. Risk perception—(3) Women acknowledged personal and fetal risk associated with participation. Acceptance of risk was influenced by women’s concepts of motherhood, preexisting knowledge of HCV and medical research, family members, intimate partners, or by the study design. Women enrolled in a phase 1 trial for chronic HCV therapy during pregnancy acknowledged risks of participation and were motivated by hopes for fetal and personal benefit and by lack of prenatal access to treatment. Ethical inclusion of pregnant people in research should acknowledge structural factors that contribute to vulnerability and data deficiencies for treatment in pregnancy.

MicroRNA 122 Affects both the Initiation and the Maintenance of Hepatitis C Virus Infections.

A liver-specific microRNA, miR-122, anneals to the hepatitis C virus (HCV) genomic 5' terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full-length RNAs with specific mutations in the 5' untranslated region (UTR) can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having encephalomyocarditis virus internal ribosomal entry site (EMCV IRES)-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by the amount of viral RNA delivered. HCV RNAs replicating independently of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of an miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication, suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection and also supports new replication complex formation during ongoing infection and after infected cell division. IMPORTANCE The mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as a potential HCV therapy.

Hepatitis C Vaccination: Where We Are and Where We Need to Be

The hepatitis C virus (HCV) is a common cause of chronic liver disease and liver cancer worldwide. Despite advances in curative therapies for HCV, the incidence of new infections is not decreasing at the expected rate to hit the World Health Organization (WHO) target for the elimination of HCV by 2030. In fact, there are still more new cases of infection in the United States and worldwide than are being cured. The reasons for the rise in new cases include poor access to care and the opioid epidemic. The clinical burden of HCV requires a multimodal approach to eradicating the infection. Vaccination would be an excellent tool to prevent incidence of new infections; however, the genetic diversity of HCV and its ability to generate quasispecies within an infected host make creating a broadly reactive vaccine difficult. Multiple vaccine candidates have been identified, but to date, there has not been a target that has led to a broadly reactive vaccine, though several of the candidates are promising. Additionally, the virus is very difficult to culture and testing candidates in humans or chimpanzees is ethically challenging. Despite the multiple barriers to creating a vaccine, vaccination still represents an important tool in the fight against HCV.

From Screening to Therapy: Anti-HCV Screening and Linkage to Care in a Network of General Practitioners and a Private Gastroenterology Practice

(1) Background: Low rates of hepatitis C virus (HCV) diagnosis and sub-optimal linkage to care constitute barriers toward eliminating the infection. In 2012/2013, we showed that HCV screening in primary care detects unknown cases. However, hepatitis C patients may not receive further diagnostics and therapy because they drop out during the referral pathway to secondary care. Thus, we used an existing network of primary care physicians and a practice of gastroenterology to investigate the pathway from screening to therapy. (2) Methods: HCV screening was prospectively included in a routine check-up of primary care physicians who cooperated regularly with a private gastroenterology practice. Anti-HCV-positive patients were referred for further specialized diagnostics and treatment if indicated. (3) Results: Seventeen primary care practices screened 1875 patients. Twelve individuals were anti-HCV-positive (0.6%), six of them reported previous antiviral HCV therapy, and one untreated patient was HCV-RNA-positive (0.05% of the population). None of the 12 anti-HCV-positive cases showed up at the private gastroenterology practice. Further clinical details of the pathway from screening to therapy could not be analyzed. (4) Conclusions: The linkage between primary and secondary care appears to be problematic in the HCV setting even among cooperating partners, but robust conclusions require larger datasets.