Hepatitis C Virus Antivirals Research Articles

Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy - data from theGerman hepatitis C registry (DHC-R).

Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

Elevated Autotaxin and LPA Levels During Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation.

Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).

Virologic Clearance of Hepatitis C Is Associated with Improved Outcomes in African American Patients with Lymphoma

Background: Association of hepatitis C virus (HCV) infection and B-cell non-Hodgkin Lymphoma (B-NHL) is well-established. Directly-acting antiviral HCV therapy (DAA) results in very high rates of sustained viral response (SVR) and HCV cure. Studies of the impact of successful antiviral therapy on lymphoma outcomes in HCV-infected patients can have important implications for patient management and for understanding of the biology of different lymphomas. The strongest evidence of positive impact of HCV antiviral therapy on lymphoma regression is available for indolent lymphomas, especially marginal zone lymphoma. Impact of antiviral therapy on HCV-associated aggressive B-NHL is still under investigation. Furthermore, there is no data on outcomes for HCV-associated B-NHL in African-American (AA) patients. The aim of this study was to evaluate lymphoma characteristics and outcomes in HCV-associated B-NHL, in a predominantly AA population. Methods: All consecutive patients with lymphoma and reactive HCV Antibody (HCV Ab+) diagnosed and treated at our center between January 2003 and December 2017 were studied. Patients with HCV-associated mixed cryoglobulinemia without any overt lymphoma, HCV-associated paraproteinemia and patients who did not have antiviral treatment history available were excluded. All information was obtained by review of electronic medical records. Baseline patient characteristics including age, sex, race, comorbidity including HIV infection, lymphoma stage, histology, prognostic score and baseline lactate dehydrogenase (LDH) were recorded. Lymphomas were classified according to the 2016 WHO classification. Prognostic score was calculated using International Prognostic Index (IPI) for aggressive lymphomas, Follicular Lymphoma International Prognostic Index (FLIPI) for indolent lymphomas other than chronic lymphocytic leukemia (CLL) and CLL-IPI for CLL. Details of lymphoma treatment and antiviral therapy were recorded. Virologic clearance (VC) was used to collectively describe both SVR (undetectable HCV RNA 12 weeks after completion of antiviral treatment) and spontaneous clearance of HCV without treatment. Study outcomes were overall response rate (ORR), complete response rate (CR), overall survival (OS) and progression free survival (PFS). Results: We found 397 patients with lymphoma at our institution, of which, 40 patients had HCV. Thirty-eight patients had complete lymphoma and antiviral treatment history available and were included in the analysis. Median age was 58 years, 90% were AA; 68% were men. Diffuse large B-cell lymphoma (DLBCL) was the predominant histology (50%). Advanced stage (64%), aggressive lymphoma (60%), good prognostic score (74%) and elevated LDH (66%) were common. A total of 21 patients were treated, 18 with DAA and 3 with interferon-based therapy. Twenty-two patients had VC, either spontaneous or with antiviral therapy. Patients with VC, had significantly higher ORR (95% vs 69%, RR 2.4, CI95 1.3-4.4, p&lt;0.05) and CR (73% vs 38%, 2.29, CI95 1.1-5.0.0, p&lt;0.05) compared to patients without VC. Median OS was also significantly higher in patients with VC than patients without VC (not reached vs 89 months, RR 0.4, CI95 0.2-0.6, p&lt;0.05) . Median PFS was not significantly different between two groups. We analyzed ORR and CR in subgroups of aggressive lymphoma, indolent lymphoma and DLBCL. Patients with VC had significantly higher CR then patients without VC in the subgroups of aggressive lymphoma and DLBCL (100% vs 46% and 100% vs 45% respectively, p&lt;0.05), while ORR was not different. Conclusions: Hepatitis C VC is associated with improved CR and OS in predominantly AA lymphoma patients including patients with aggressive B-NHL. The precise role and timing of HCV antiviral therapy in HCV-associated aggressive B-NHL should be assessed in large prospective studies that include AA patients. Disclosures No relevant conflicts of interest to declare.

Customized hepatocellular carcinoma prediction panel

Abstract Background West Africa is a hotbed of hepatocellular carcinoma (HCC) partly due to aflatoxin B (AFB) contamination. In Russia, there is now a pool of patients who have liver cirrhosis due to hepatitis C virus (HCV), who were treated with direct antiviral agents and HCV negative, but due to cirrhosis are in the risk group for HCC development. MiRNAs are candidate molecules for HCC prediction panel. The question is if it is possible to use the same miRNAs for HCC development risk despite background or it is reasonable to have a special miRNA set according to background (for example, HCC, HBV, continuous AFB consumption etc.). Methods Samples from Somalia: 40 plasmas of HCV negative patients with HCC, 8 plasmas of HCV positive patients with HCC, 22 plasmas of HCV-negative patients with liver cirrhosis, 8 plasmas of HCV-positive patients with liver cirrhosis, 11 plasmas from healthy students living outside West Africa last 9-12 months as control group. Samples from Russia: 12 plasmas of patients with HCC (HCV+ and HCV-) and 30 plasmas of patients with liver cirrhosis, 11 plasmas from healthy donors as control group. Exosomes were isolated from plasma by differential ultracentrifugation following free-flow electrophoresis. MiRNA let-7a-5p, -224-5p, -106b-3p, -126-5p, -122-5p, -16-5p and -34a-5p were determined in exosomes by qPCR-RT. Same free miRNA from plasma were determined. Plasma samples were examined for AFB1. Results There is an interesting tendency for miRNA-21 and mi-RNA-122: on the stage of cirrhosis in Somalian samples there is a significant difference in expression levels that disappears on the HCC stage. Profiles of free miRNAs circulating in plasma were not significantly different between the groups. There was a difference in exosomal miRNA profile of plasma from patients with HCC and cirrhosis for both (Russia and Somalia) group of samples. Conclusions The difference in miRNA profiles of HCC patients on the background of HCV or aflatoxins consumption may allow supposing different epigenetics dysregulation happening in HCC depending on the trigger factor. According to our results, exosomal miRNA identification in HCC patients seem to be more accurate than plasma free miRNAs and it seems reasonable to modify biomarker panel for HCC risk according to the case background it is intended to work for. Legal entity responsible for the study The authors. Funding Ministry of Science and Higher Education of the Russian Federation Project 5-100. Disclosure All authors have declared no conflicts of interest.

Autoimmune hepatitis associated Hepatitis C virus infection treated with fi rst generation direct-acting antivirals

The hepatitis C virus (HCV) infection has been associated with autoimmune diseases, probably due to the interaction between HCV E2 envelope protein and CD-81 receptor of B lymphocyte and thus, can infl uence the pathogenesis of autoimmune liver diseases [1,2]. Therefore, it seems reasonable to consider the benefi cial effect of direct-acting antivirals (DAAs) for HCV in patients with chronic HCV infection and autoimmune hepatitis (HAI), although evidence is scarce.

Impact of pill burden on adherence to hepatitis C medication

Objective: To describe pill burden before and after hepatitis C virus (HCV) treatment initiation among patients newly treated for HCV infection, and to evaluate the association between HCV pill burden and gaps in HCV therapy.Methods: This was a retrospective administrative claims study of patients treated with direct-acting antivirals (DAAs) for HCV from 1 November 2013 to 31 July 2016. HCV pill burden was defined as the pill count per day for the index HCV regimen. Mean overall pill burden (HCV medications plus non-HCV medications) was calculated in the 90 days before and after DAA initiation. Gaps in the index HCV regimen were assessed in the 6 months after DAA initiation. Multivariable logistic regression was used to compare the odds of a gap in HCV therapy across HCV pill burden categories (1 pill/day, 2 pills/day, and ≥3 pills/day).Results: Among 9815 patients who met the study criteria, mean overall pill burdens before and after DAA treatment initiation were 5.4 and 7.7, respectively (p < .001). The adjusted odds ratio (OR) of a ≥15-day gap in HCV therapy was 1.75 (95% confidence interval [CI] = 1.38–2.22) for patients with 2 HCV pills/day and 2.11 (95% CI = 1.78–2.51) for patients with ≥3 pills/day, compared with patients with 1 HCV pill/day.Conclusions: Patients with HCV have a substantial pill burden even before initiating HCV treatment. As higher HCV pill burden was associated with lower medication adherence, pill burden should be an important consideration in HCV treatment selection.

Replicons of a Rodent Hepatitis C Model Virus Permit Selection of Highly Permissive Cells.

Animal hepaciviruses represent promising surrogate models for hepatitis C virus (HCV), for which there are no efficient immunocompetent animal models. Experimental infection of laboratory rats with rodent hepacivirus isolated from feral Rattus norvegicus (RHV-rn1) mirrors key aspects of HCV infection in humans, including chronicity, hepatitis, and steatosis. Moreover, RHV has been adapted to infect immunocompetent laboratory mice. RHV in vitro systems have not been developed but would enable detailed studies of the virus life cycle crucial for designing animal experiments to model HCV infection. Here, we established efficient RHV-rn1 selectable subgenomic replicons with and without reporter genes. Rat and mouse liver-derived cells did not readily support the complete RHV life cycle, but replicon-containing cell clones could be selected with and without acquired mutations. Replication was significantly enhanced by mutations in NS4B and NS5A and in cell clones cured of replicon RNA. These mutations increased RHV replication of both mono- and bicistronic constructs, and CpG/UpA-dinucleotide optimization of reporter genes allowed replication. Using the replicon system, we show that the RHV-rn1 NS3-4A protease cleaves a human mitochondrial antiviral signaling protein reporter, providing a sensitive readout for virus replication. RHV-rn1 replication was inhibited by the HCV polymerase inhibitor sofosbuvir and high concentrations of HCV NS5A antivirals but not by NS3 protease inhibitors. The microRNA-122 antagonist miravirsen inhibited RHV-rn1 replication, demonstrating the importance of this HCV host factor for RHV. These novel RHV in vitro systems will be useful for studies of tropism, molecular virology, and characterization of virus-host interactions, thereby providing important complements to in vivo systems.IMPORTANCE A vaccine against hepatitis C virus (HCV) is crucial for global control of this important pathogen, which induces fatal human liver diseases. Vaccine development has been hampered by the lack of immunocompetent animal models. Discovery of rodent hepacivirus (RHV) enabled establishment of novel surrogate animal models. These allow robust infection and reverse genetic and immunization studies of laboratory animals, which develop HCV-like chronicity. Currently, there are no RHV in vitro systems available to study tropism and molecular virology. Here, we established the first culture systems for RHV, recapitulating the intracellular phase of the virus life cycle in vitro These replicon systems enabled identification of replication-enhancing mutations and selection of cells highly permissive to RHV replication, which allow study of virus-host interactions. HCV antivirals targeting NS5A, NS5B, and microRNA-122 efficiently inhibited RHV replication. Hence, several important aspects of HCV replication are shared by the rodent virus system, reinforcing its utility as an HCV model.

Adoption of direct-acting antiviral medications for hepatitis C: a retrospective observational study

BackgroundApproximately 3.5 million Americans are infected with the hepatitis C virus (HCV). Although many patients with HCV are asymptomatic, HCV is the leading cause of infection-related death in the U.S. With advances in curative medication therapy for HCV, many of these deaths are preventable. Access to innovative therapies may be unevenly distributed. Our objective was to describe medication prescribers’ adoption of innovative HCV pharmacotherapy across prescriber, geographical location, and time.MethodsThis is a retrospective, secondary data analysis among a national cohort of patients prescribed direct-acting antiviral HCV medications with curative intent. We assessed prescriptions by time, geographic location, and provider type.ResultsThe peak of the adoption rate occurred within 45 days; nearly one-sixth of all prescribers had already prescribed one of the new drugs. Geographical regions (Midwest, South, and West all p ≥ 0.05) nor gender (p = 0.455) of a prescriber impacted adoption. Similarly, patient income did not influence the likelihood of a prescriber to adopt the new drugs earlier (p = 0.175). Gastroenterologists or hepatologists were more likely earlier adopters compared to primary care physicians (p = 0.01).ConclusionsBecause of the relative advantage of newer therapies, we anticipated that there would be an initial surge as early adopters prescribed the new medications and use would dwindle over time as the initial HCV cohort was cured. The data demonstrate that our hypothesis is essentially supported. There is a reduction in prescriptions at approximately 5 months post-approval and treatment is typically required for 3 months. There has been a surge in clinicians’ adoption of innovative HCV treatments. As patients are cured of their infection, we anticipate a decreased need for chronic management of HCV.Trial registrationNot applicable.KeywordsDissemination researchHealth services researchInfectious diseaseHepatitis C

The Changing Face of Liver Transplantation in the United States: The Effect of HCV Antiviral Eras on Transplantation Trends and Outcomes.

BackgroundHepatitis C virus (HCV) cirrhosis is the leading indication for liver transplantation in the United States, although nonalcoholic steatohepatitis (NASH) is on the rise. Increasingly effective HCV antivirals are available, but their association with diagnosis-specific liver transplantation rates and early graft survival is not known.MethodsThe Scientific Registry of Transplant Recipients database records were retrospectively stratified by HCV antiviral era: interferon (2003-2010), protease inhibitors (2011-2013), and direct-acting antivirals (2014 to present). Kaplan-Meier, χ2, and multivariable Cox proportional hazards regression models evaluated the effects of antiviral era and etiology of liver disease on transplantation rates and graft survival over 3 years.ResultsLiver transplants for HCV decreased (35.3% to 23.6%), whereas those for NASH and alcoholic liver disease increased (5.8% to 16.5% and 15.6% to 24.0%) with each advancing era (all P < 0.05). Early graft survival improved with each advancing era for HCV but not for hepatitis B virus, NASH, or alcoholic liver disease (multivariable model era by diagnosis interaction P < 0.001). Era-specific multivariable models demonstrated that the risk of early graft loss for NASH was 22% lower than for HCV in the interferon era (hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; P = 0.02) but risks associated with these diagnoses did not differ significantly in the protease inhibitor (P = 0.06) or direct-acting antiviral eras (P = 0.08).ConclusionsIncreasing effectiveness of HCV antivirals corresponds with decreased rates of liver transplantation for HCV and improved early graft survival. As the rates of liver transplant for NASH continue to increase, focus will be needed on the prevention and effective therapies for this disease.

Priorities and recommended actions for how researchers, practitioners, policy makers, and the affected community can work together to improve access to hepatitis C care for people who use drugs

It is estimated that 6.1 million people with recent injecting drug use (PWID) are living with hepatitis C virus (HCV). Although HCV-related morbidity and mortality among PWID continues to increase, the advent of direct acting antiviral (DAA) HCV regimens with cure rates >95% provides an opportunity to reverse the rising burden of disease. Additionally, given evidence that opioid substitution therapy and high-coverage needle and syringe programs can reduce HCV incidence by up to 80%, there is an opportunity to reduce HCV transmission with increased coverage of harm reduction services. However, there are significant patient, provider, health system, structural, and societal barriers that impede access to HCV prevention and care for PWID. The International Network on Hepatitis in Substance Users (INHSU), in collaboration with the Australasian Society for HIV, Viral Hepatitis, Sexual Health Medicine (ASHM), Harm Reduction International, the Canadian Network on Hepatitis C, Canadian Research Initiative in Substance Misuse, the National Viral Hepatitis Roundtable, Médecins du Monde and CATIE, held a roundtable discussion prior to the Harm Reduction Conference in Montreal, Canada on 13th May 2017 to discuss how to improve HCV prevention and care for PWID. Over 100 international researchers, practitioners, policy makers, advocates, and affected community members came together to discuss shared priorities for action, develop actionable next steps and to create partnerships to enable application of priorities. This paper highlights the key priority areas identified by participants including: enhancing global coverage of harm reduction services; addressing punitive drug policies; ensuring access to affordable HCV diagnostics and treatment; improving the evidence-base for HCV prevention, testing, linkage to care and treatment; implementing integrated HCV programs; advancing peer-based models of HCV care; and tackling social determinants of health inequalities for PWID. This paper also highlights the recommended actions for each priority identified by the participants from this roundtable.

Telementoring for hepatitis C treatment in correctional facilities

Introduction Prevalence of hepatitis C virus (HCV) is substantially higher among prisoners than the general population. In Australia until recently, only a small proportion of prisoners with HCV received antiviral therapy. The direct-acting antivirals (DAAs) for HCV are highly effective, with a low burden of side effects. Since 2016, DAAs are available to all Australians with HCV. However, currently in Australia, they can only be prescribed by or in consultation with experienced prescribers. This study evaluated a telementoring service to upskill doctors and nurse practitioners working in correctional facilities. Methods The telementoring service was implemented in five correctional facilities. Qualitative interviews were used to examine the perceived clinical effectiveness and organisational impacts of the service. Content analysis of the interviews was used to identify key themes. Results In the first ten months of the service, there were 16 telementoring sessions with 173 patients discussed. Sixteen staff participated in qualitative interviews. From these, three key themes were identified: access to antiviral therapy; organisational impacts (cost, increased staff knowledge and confidence, staff time, and workload); and, adaptations of the care model and future opportunities. Conclusion Telementoring is an effective method to facilitate eligible prescriber status to medical doctors and upskill other clinicians in correctional facilities to increase capacity to treat HCV.

Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations.

Worldwide, more than one million people die each year from hepatitis C virus (HCV) related diseases, and over 300 million people are chronically infected with hepatitis B or C. Egypt used to be on the top of the countries with heavy HCV burden. Some countries are making advances in elimination of HCV, yet multiple factors preventing progress; remain for the majority. These factors include lack of global funding sources for treatment, late diagnosis, poor data, and inadequate screening. Treatment of HCV in Egypt has become one of the top national priorities since 2007. Egypt started a national treatment program intending to provide cure for Egyptian HCV-infected patients. Mass HCV treatment program had started using Pegylated interferon and ribavirin between 2007 and 2014. Yet, with the development of highly-effective direct acting antivirals (DAAs) for HCV, elimination of viral hepatitis has become a real possibility. The Egyptian National Committee for the Control of Viral Hepatitis did its best to provide Egyptian HCV patients with DAAs. Egypt adopted a strategy that represents a model of care that could help other countries with high HCV prevalence rate in their battle against HCV. This review covers the effects of HCV management in Egyptian real life settings and the outcome of different treatment protocols. Also, it deals with the current and future strategies for HCV prevention and screening as well as the challenges facing HCV elimination and the prospect of future eradication of HCV.

Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid.

AIMTo investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODSThe antiviral activity of daclatasvir (DCV) and asunaprevir (ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus (HCV) infection.RESULTSTacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid (MPA) showed additive antiviral effects combined with these direct acting antivirals (DAAs). MPA induces interferon-stimulated genes (ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.CONCLUSIONImmunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

Clinical features and management of oral lichen planus (OLP) with emphasis on the management of hepatitis C virus (HCV)-related OLP.

Oral lichen planus (OLP) is a chronic inflammatory disease characterized by the occurrence of multiple, symmetrical lesions in the oral cavity. Hepatitis C virus (HCV) infection has been suggested as an etiological factor in OLP. The purpose of this review was to summarize the current literature regarding the treatment of OLP in patients with HCV infection. An electronic search of the PubMed database was conducted until January 2018, using the following keywords: OLP, HCV, corticosteroids, retinoids, immunomodulatory agents, surgical interventions, photochemotherapy, laser therapy, interferon, ribavirin, and direct-acting antivirals. We selected the articles focusing on the clinical features and treatment management of OLP in patients with/without HCV infection. Topical corticosteroids are considered the first-line treatment in OLP. Calcineurin inhibitors or retinoids can be beneficial for recalcitrant OLP lesions. Systemic therapy should be used in the case of extensive and refractory lesions that involve extraoral sites. Surgical intervention is recommended for isolated lesions. In patients with HCV, monotherapy with interferon (IFN)-α may either improve, aggravate or trigger OLP lesions, while combined IFN-α and ribavirin therapy does not significantly influence the progression of lesions. Direct-acting antiviral (DAA) therapy appears to be a promising approach in patients with HCV-related OLP, as it can improve symptoms of both liver disease and OLP, with fewer side effects. Nevertheless, for clinical utility of DAAs in OLP patients, further studies with larger sample sizes, adequate treatment duration, and long term follow-up are required.

Diagnosis and treatment of hepatitis C virus infection: a tool for engagement with people who inject drugs in Vancouver's Downtown Eastside.

Vancouver's Downtown Eastside (DTES) faces the interrelated challenges of poverty, homelessness, mental health, addiction, and medical issues such as hepatitis C virus (HCV). This study evaluates a new model of engagement with people who inject drugs (PWID) in the DTES. Our centre has developed the community pop-up clinic (CPC) to engage vulnerable populations such as PWID. Rapid HCV testing is offered using the OraQuick saliva assay. If a test is positive, immediate medical consultation and an incentivized clinic appointment are offered. At this appointment, an HCV treatment plan is developed, along with a plan for engagement in multidisciplinary care. In 12 months, 1,283 OraQuick tests were performed at 44 CPCs; 21% of individuals were found to be positive for HCV (68% of whom were PWID). Of individuals positive for HCV antibodies who consulted with the on-site doctor, 50% engaged in care in our clinic-61% of whom have initiated interferon-free directly acting antiviral (DAA) HCV therapy with 100% cured of HCV (per protocol). Individuals who did not engage in care were significantly more likely to be homeless (P < .0001). CPCs paired with a multidisciplinary model of care address the needs of vulnerable populations such as PWID, particularly in the management of HCV with interferon-free DAA therapies.

Cost-effectiveness of using kidneys from hepatitis C nucleic acid test-positive donors for transplantation in hepatitis C-negative recipients.

Kidneys from deceased donors who are hepatitis C virus (HCV) nucleic acid test positive are infrequently used for transplantation in HCV-negative patients due to concerns about disease transmission. With the development of direct-acting antivirals (DAAs) for HCV, there is now potential to use these kidneys in HCV-negative candidates. However, the high cost of DAAs poses a challenge to adoption of this strategy. We created a Markov model to examine the cost-effectiveness of using deceased donors infected with HCV for kidney transplantation in uninfected waitlist candidates. In the primary analysis, this strategy was cost saving and improved health outcomes compared to remaining on the waitlist for an additional 2 or more years to receive a HCV-negative transplant. The strategy was also cost-effective with an incremental cost-effectiveness ratio of $56018 per quality-adjusted life year (QALY) from the payer perspective, and $4647 per QALY from the societal perspective, compared to remaining on the waitlist for 1 additional year. The results were consistent in 1-way and probabilistic sensitivity analyses. We conclude that the use of kidneys from deceased donors with HCV infection is likely to lead to improved clinical outcomes at reduced cost for HCV-negative transplant candidates.

Real-world Efficacy of Direct-Acting Antiviral Therapy for HCV Infection Affecting People Who Inject Drugs Delivered in a Multidisciplinary Setting.

BackgroundMany clinicians and insurance providers are reluctant to embrace recent guidelines identifying people who inject drugs (PWID) as a priority population to receive hepatitis C virus (HCV) treatment. The aim of this study was to evaluate the efficacy of direct-acting antiviral (DAA) HCV therapy in a real-world population comprised predominantly of PWID.MethodsA retrospective analysis was performed on all HCV-infected patients who were treated at the Vancouver Infectious Diseases Centre between March 2014 and December 2017. All subjects were enrolled in a multidisciplinary model of care, addressing medical, psychological, social, and addiction-related needs. The primary outcome was achievement of sustained virologic response (undetectable HCV RNA) 12 or more weeks after completion of HCV therapy (SVR-12).ResultsOverall, 291 individuals were enrolled and received interferon-free DAA HCV therapy. The mean age was 54 years, 88% were PWID, and 20% were HCV treatment experienced. At data lock, 62 individuals were still on treatment and 229 were eligible for evaluation of SVR by intent-to-treat (ITT) analysis. Overall, 207 individuals achieved SVR (90%), with 13 losses to follow-up, 7 relapses, and 2 premature treatment discontinuations. ITT SVR analysis show that active PWID and treatment-naïve patients were less likely to achieve SVR (P = .0185 and .0317, respectively). Modified ITT analysis of active PWID showed no difference in achieving SVR (P = .1157) compared with non-PWID.ConclusionWithin a multidisciplinary model of care, the treatment of HCV-infected PWID with all-oral DAA regimens is safe and highly effective. These data justify targeted efforts to enhance access to HCV treatment in this vulnerable and marginalized population.

Challenges Facing a Rural Opioid Epidemic: Treatment and Prevention of HIV and Hepatitis C.

This article reviews recent epidemiologic trends in HIV and hepatitis C virus (HCV) and strategies for treatment and prevention of these infections as they relate to the opioid epidemic. Among people who inject drugs (PWID) in the United States (US), HIV diagnoses are decreasing, while HCV is increasing. Care for HIV and HCV relies heavily on specialist infrastructure, which is lacking in rural areas. Antiretrovirals for HIV and direct-acting antivirals for HCV are effective among PWID, yet multiple barriers make it difficult for rural injectors to access these treatments. Similarly, access to syringe service programs, medication-assisted therapy for opioid addiction, and pre-exposure prophylaxis for HIV are all limited in rural areas. Previous research on HIV and HCV among PWID has focused on urban or international populations, yet the US opioid epidemic is moving away from metropolitan centers. Increasing rurality of opioid injection brings unique challenges in treatment and prevention. Research into the care of HIV, HCV, and opioid use disorder among rural populations is urgently needed.

IN3 - Incidence of Hepatocellular Carcinoma and Extrahepatic Cancers Among HCV-Infected Patients in the Era of Direct-Acting Antivirals

Hepatitis C virus (HCV) infection is associated with increased risks of hepatocellular carcinoma (HCC) and non-hepatic cancers. However, it is unclear whether the new direct-acting antivirals (DAAs) for HCV reduce the incidence of these malignancies. This study aims to examine the impact of DAA treatment on the incidence of HCC and non-hepatic cancers among HCV patients in the U.S. A retrospective cohort analysis of the Truven Health MarketScan Database (January 2008- August 2015) was conducted. We included adult patients with newly diagnosed HCV and without a history of cancer. We followed patients from the first HCV diagnosis to the end of enrollment or the occurrence of outcomes, including HCC and non-hepatic cancers. To assess the association between DAA treatment and the risk of developing cancers, a time-varying exposure analysis was performed. We employed cox proportional hazards models to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs). Baseline demographics and comorbidities such as cirrhosis, HBV, HIV, and drug abuse were adjusted in all models. We identified a total of 46,361 HCV-infected patients (mean age= 52yrs, 61% male), among which 4,311 patients (9.3%) initiated DAA therapy whereas 42,050 (90.7%) patients did not receive any HCV treatment. DAA-treated patients had a higher crude incidence of HCC compared with untreated patients (1,380 vs. 977 per 100,000 person-years), but a lower incidence of non-hepatic cancers (745 vs. 1,216 per 100,000 person-years). After baseline adjustment, patients who received DAA therapy had a 21% decreased the risk of developing HCC (HR=0.79, 95% CI=0.55-1.09) compared to untreated patients, although this was not statistically significant. DAA therapy significantly decreased the risk of developing non-hepatic cancers by 63% (HR=0.37, 95% CI=0.23-0.57). DAA treatment is associated with a decreased incidence of non-hepatic cancers among HCV patients, although the association with HCC is not statistically significant.

Transmission genetics of drug-resistant hepatitis C virus.

Antiviral development is plagued by drug resistance and genetic barriers to resistance are needed. For HIV and hepatitis C virus (HCV), combination therapy has proved life-saving. The targets of direct-acting antivirals for HCV infection are NS3/4A protease, NS5A phosphoprotein and NS5B polymerase. Differential visualization of drug-resistant and -susceptible RNA genomes within cells revealed that resistant variants of NS3/4A protease and NS5A phosphoprotein are cis-dominant, ensuring their direct selection from complex environments. Confocal microscopy revealed that RNA replication complexes are genome-specific, rationalizing the non-interaction of wild-type and variant products. No HCV antivirals yet display the dominance of drug susceptibility shown for capsid proteins of other viruses. However, effective inhibitors of HCV polymerase exact such high fitness costs for drug resistance that stable genome selection is not observed. Barriers to drug resistance vary with target biochemistry and detailed analysis of these barriers should lead to the use of fewer drugs.