Hepatitis C Virus Regimens Research Articles

Outcomes of early vs late treatment initiation in solid organ transplantation from hepatitis C virus nucleic acid test-positive donors to hepatitis C virus-uninfected recipients: Results from the HCV-TARGET study

Curative hepatitis C virus (HCV) therapy has increased transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients (D+/R-). We evaluated outcomes of early and late HCV treatment among D+/R- nonliver organ transplants. Patients received HCV regimens per local standard (n = 10 sites). Outcomes were compared between early and late treatments. Early treatment regimens (ETR) (n = 56) were initiated pretransplantation to day 7 posttransplant. Late treatment regimens (LTRs) (n = 102) began median 31 (range, 8-114) days posttransplant. There were 79 kidney, 50 lung, 23 heart, and 6 mixed transplants, similar between groups. HCV RNA was quantifiable in 98% of LTR versus 44.6% of ETR recipients (P < .001). Mean (range) days on treatment were 28 (7-93) ETR and 81 (51-111) LTR (P < .0001). There were no virological failures with ETR, but relapse (n = 3) and nonresponse (n = 2) in LTR (P = .16), including fibrosing cholestatic hepatitis postrelapse (n = 1). Sustained virological response was 100% (95% confidence interval, 93.4-100.0) in ETR (n = 54) and 94.9% (95% confidence interval, 88.5-98.3) in LTR (n = 98). Acute rejection occurred in 11 (19.6%) ETR and 25 (24.5%) LTR. In total, 11 HCV-unrelated deaths occurred: 8 ETR and 3 LTR. Organ transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients was safe. ETR led to fewer virological failures with shorter treatment duration, supporting recommendations to initiate treatment promptly posttransplant.

Evaluation of Drug Interactions in Patients Treated with DAAs for Hepatitis C Therapy with Comorbidities and Cardiovascular Issues—A Delphi Consensus Project

Orally administered direct-acting antivirals (DAAs) have dramatically changed the possibility of curing HCV (hepatitis C virus) infection, with the two principal HCV regimens based on the combination of glecaprevir + pibrentasvir (GLE-PIB) and sofosbuvir + velpatasvir (SOF-VEL). A combination of drugs containing NS3/4A protease inhibitors, as well as the fact that almost all HCV patients can be treated at present, may expose patients to a higher rate of drug-drug interactions (DDIs). The hepatitis C treatment recommendations from the EASL (European Association for the Study of the Liver) state that, prior to starting treatment with a DAA, a detailed drug history should be taken; yet, the decision on managing the potential DDIs is not always clear. For this reason, a group of Italian cardiologists and hepatologists promoted a survey among colleagues to assess the controversial issues when treating patients with chronic hepatitis C taking concomitant cardiovascular drugs, aiming to reach a consensus on the best practice to apply when treating a patient with chronic hepatitis C who is taking concomitant drugs for cardiovascular diseases. Two consecutive questionnaires were proposed between June and July 2022 to a qualitative Expert Panel (EP) of 14 gastroenterologists, infectologists, hepatologists, and internists, with statistical analyses performed on 100% of the responses for both questionnaires. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The interviewed experts consider DDIs a critical clinical problem to be evaluated in HCV patients. Therefore, dose changes, drug substitution, and discontinuation of concomitant cardiovascular drugs should be discouraged, even if planned for a relatively short period. Since oral DAAs have different DDIs profiles, hepatologists should prefer the antiviral DAA combination presenting the lowest instance of potential interactions.

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery.

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 μg/mL at pH 1-6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Effect of different direct-acting antiviral regimens for treatment of nondiabetic hepatitis C virus\u2013infected Egyptian patients on insulin resistance and sensitivity

BackgroundThe association between hepatitis C virus (HCV), insulin resistance (IR), and metabolic syndrome has been extensively investigated. Direct-acting antivirals (DAAs) have a high sustained virologic response (SVR) rate, reaching > 90%. The effect of SVR after DAA treatment on metabolic parameters and IR in nondiabetic patients could be an important factor in the patient’s long-term outcome. The aim of the study is to evaluate the impact of different DAA regimens on IR and sensitivity in naïve chronic HCV-infected nondiabetic patients (before and after 12 weeks of treatment).MethodsThis prospective cohort study was conducted on 100 HCV-infected Child A nondiabetic patients eligible for DAA treatment in the Department of Gastroenterology and Hepatology, Ain Shams University, and Kobry El-Kobba Military Hospital among patients attending the outpatient clinic.Patients were categorized into four groups according to the HCV regimens they received for 12 weeks.All patient were subjected to the following tests before and 12 weeks after treatment: HCV quantitative PCR, Fibroscan, fasting insulin level (using insulin quantitative test kit), fasting and postprandial blood glucose (PPG), lipid profile, liver enzymes, BMI, and waist circumference.ResultsAll patients achieved SVR at 12 weeks. In all treatment groups, lab was assessed before and after treatment, the 2-h PPG, high-density lipoprotein, and low-density lipoprotein levels showed statistically significant increases, whereas triglyceride, fasting glucose, hemoglobin A1C, and fasting plasma insulin levels showed statistically significant decreases. The homeostasis model assessment of insulin resistance (HOMA-IR) exhibited statistically significant decreases, whereas the quantitative insulin sensitivity check index (QUICKI) and Matsuda index showed statistically significant increases, across the four groups.ConclusionsDAA treatment in naïve nondiabetic HCV-infected patients affects metabolic profile and insulin resistance/sensitivity, with similar effect among different DAA regimens.

Hepatitis B and C during pregnancy

The purpose of this article is to provide a comprehensive overview of current knowledge about pregnancy and hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and current methods to reduce mother-to-child transmission (MTCT). Maternal infection with HBV or HCV is associated with complicated pregnancy and childbirth outcomes, including MTCT. In countries, including the United States, which introduced postpartum HBV vaccination and immunization with hepatitis B immunoglobulin, MTCT overall decreased to about 5%. However, with maternal HBV levels greater than 200,000 IU/ml, the transmission rate of HBV to neonates is almost 30%. For these patients, there are new recommendations from the European Association for the Study of the Liver (EASL), which indicate that, in addition to vaccination of newborns and their immunization, treatment with antiviral drugs such as tenofovir disoproxil fumarate or telbivudine, used during pregnancy, starting from 32 weeks is necessary, that are safe and effective in preventing mother-to-child transmission. Unlike HBV, no therapy is yet available or recommended to further reduce the risk of mother-to-child transmission of HCV infection, which remains by 310%. MTCT of HCV can be minimized by avoiding obstetrics and birth trauma if possible. Young women with HCV should be sent for treatment after delivery, and newborns should be closely monitored to rule out infection. Newer, better tolerated HCV regimens have become more available and should reduce the number of women and babies infected.

Prevalence of resistance-associated substitutions and phylogenetic analysis of hepatitis C virus infection in Russia

ObjectivesDue to limited hepatitis C virus (HCV) sequence availability from patients in Russia, the relationship between subtypes and baseline resistance-associated substitutions (RAS) to direct antiretroviral treatment outcome is not fully understood. MethodsDeep sequencing of HCV NS3, NS5A, and NS5B sequences was performed on plasma HCV samples from 412 direct-acting antiviral (DAA)-naïve patients from Russia. Phylogenetic analysis was performed to investigate sequence similarities between HCV strains from Russia, Asia, Europe, and North America. Pretreatment HCV RAS was assessed with a 15% cutoff. ResultsHCV genotype GT1b and GT3a sequences in Russia were related to strains in Europe and Asia. The prevalence of GT1a and GT2a was low in Russia. In GT1b, the prevalence of NS5A Y93H was lower in Russia (6%) compared with Asia (15%). The prevalence of NS5B L159F was similar between Russia and Europe (26–39%). GT3a RAS prevalence was similar between Russia and Asia, Europe, and North America. The 2k/1b recombinant strain in Russia was related to strains from Europe. A higher prevalence of the NS5A RAS L31M (10%) was observed in 2k/1b sequences compared to GT1b (1–6%). ConclusionsThe prevalence of RASs and the phylogenetic analysis showed similarities in HCV strains between Russia, Europe, and North America. This information may be useful for HCV regimens in Russia.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

Efficacy of DAAs in the Treatment of Chronic HCV: Real-World Data from the Private Health-Care Sector of the Kingdom of Saudi Arabia

Background and AimThe hepatitis C virus (HCV) is considered a global health challenge that requires urgent interventions for prevention and control. In this study, we aimed to evaluate the effectiveness of direct-acting antiviral agents (DAAs) for HCV-infected patients in the Kingdom of Saudi Arabia (KSA).Patients and MethodsIn this retrospective cohort study, we ascertained data of patients treated with DAA-based regimens for chronic HCV in the private health-care sector hospitals of KSA between April 2015 and December 2017. Data regarding presence or absence of liver cirrhosis, virus genotype, quantitative HCV RNA test, fibrosis stage, and history of liver disease were included. The primary end point of the study was the overall cure rate, defined as the number of patients achieving sustained viral response (SVR) rate at least 12 weeks following completion of treatment, divided by the total number of patients included in the study.ResultsA total of 262 patients fulfilled the study inclusion criteria. Adult patients were enrolled, of which 114 (44%) were females and 148 (56%) were males. About 105 of the patients (40%) were cirrhotic and 156 were treatment-naïve patients (60%), 84 patients were interferon (INF) experienced, and 22 patients had previously received new DAAs but failed to achieve SVR. The majority of patients received ledipasvir–sofosbuvir±RBV (57%) with SVR rate of approximately 97%.ConclusionsOur local real-world data indicate an overall HCV cure rate of 97% following treatment with DDA’s when prescribed in the private sector. This estimate is acquiescence with previously reported global cure rates.

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.

A Pharmacology Perspective of Simultaneous Tuberculosis and Hepatitis C Treatment.

Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs) and existing data precludes these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move co treatment regimens forward for clinical use among patients coinfected with TB and HCV.

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.

Influential Factors of Successful Hepatitis C Treatment in Elderly Patients.

Chronic Hepatitis C virus (HCV) is an infection associated with an increased risk of cirrhosis, hepatocellular carcinoma (HCC), and morbidity and mortality. Treating HCV poses challenges in the elderly population due to the lack of evidence and complexity of patients. This study aims to evaluate factors that influence HCV treatment success in elderly patients, especially those over age of 70, such as pill burden and comorbidities, in addition to drug interactions and adverse effects. This was a retrospective chart review of patients treated at our urban academic institution from 2014-2016. Sixty-two patients over the age of 70 were included in this study. The sustained virologic response rate 12 weeks after the completion of treatment (SVR12) was 79%. In a multi-variate analysis, cirrhosis, age closer to 70, and longer duration of treatment were statistically significantly more likely to lead to treatment failure. Though not statistically significant, other factors that may negatively influence achievement of SVR12 were cognitive impairment, cardiovascular disease, multi-tablet HCV regimen, time to initiation of HCV treatment > 90 days, and prior treatment experience. Pill burden of other prescribed medications did not impact SVR12. Adverse events and drug interactions were common in the population. Overall SVR12 rate in the elderly population was lower than that reported in the literature. Factors associated with lower treatment success, especially cirrhosis, should be considered when treating an elderly population. Further data is needed on the impact of other factors on SVR12 attainment in an elderly patient population.

Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

BackgroundWe conducted a pilot study assessing the feasibility, efficacy, and safety of a simplified combination HIV antiretroviral and hepatitis C virus (HCV) antiviral regimen in HIV–HCV coinfection.MethodsParticipants on suppressive antiretrovirals and HCV genotype 1 infection were switched to single-tablet daily-dosed elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and 1 month later initiated single-tablet-regimen daily-dosed ledipasvir-sofosbuvir for 12 weeks. E/C/F/TAF was continued during HCV treatment and for 12 weeks after.ResultsTwenty-six individuals were screened, 25 enrolled, and 23 completed all HIV and HCV treatment. Participants were predominantly male, with a mean age (SD) of 55 (7.5) years. The median transient elastography score (interquartile range [IQR]) was 5.9 (5.3 to 7.6) kPa, and the mean CD4 count (SD) was 579 (223) cells/µL. The median adherence to HCV medications, assessed by pill count, was 100% (95% confidence interval [CI], 100%–100%), and HIV ranged from 99% to 100% (100%; 95% CI, 90%–100%) over the 7-month study duration. HIV undetectability was maintained in all but 1 participant enrolled with unsuspected multiclass resistance. Treatment was well tolerated, with no study medication modification due to adverse events and no serious adverse event related to the study drug. All participants achieved sustained virological response. The mean CD4 count (SD) increased to 673 (361) cells/µL, and the fibrosis score (IQR) declined to 5.2 (4.4 to 7.4) kPa by week 12 after HCV treatment. There was no treatment effect on glucose metabolism. Cholesterol increased during and after treatment.ConclusionsProvision of this 2-tablet daily HIV–HCV regimen is feasible, well tolerated, and safe, avoids drug–drug interactions between HIV and HCV medications, maintains HIV suppression in the absence of drug resistance, and is highly curative of HCV.

Direct-Acting Antiviral Treatment Failure Among Hepatitis C and HIV-Coinfected Patients in Clinical Care.

BackgroundThere are limited data on the real-world effectiveness of direct-acting antiviral (DAA) treatment in patients coinfected with hepatitis C virus (HCV) and HIV—a population with complex challenges including ongoing substance use, cirrhosis, and other comorbidities. We assessed how patient characteristics and the appropriateness of HCV regimen selection according to guidelines affect treatment outcomes in coinfected patients.MethodsWe included all patients who initiated DAA treatment between November 2013 and July 2017 in the Canadian Co-Infection Cohort. Sustained virologic response (SVR) was defined as an undetectable HCV RNA measured between 10 and 18 weeks post-treatment. We defined treatment failure as virologic failure, relapse, or death without achieving SVR. Bayesian logistic regression was used to estimate the posterior odds ratios (ORs) associated with patient demographic, clinical, and treatment-related risk factors for treatment failure.ResultsTwo hundred ninety-five patients initiated DAAs; 31% were treatment-experienced, 29% cirrhotic, and 80% HCV genotype 1. Overall, 92% achieved SVR (263 of 286, 9 unknown), with the highest rates in females (97%) and lowest in cirrhotics (88%) and high-frequency injection drug users (89%). Many patients (38%) were prescribed regimens that were outside current clinical guidelines. This did not appreciably increase the risk of treatment failure—particularly in patients with genotype 1 (prior odds ratio [OR], 1.5; 95% credible interval [CrI], 0.38–6.0; posterior OR, 1.0; 95% CrI, 0.40–2.5).ConclusionsDAAs were more effective than anticipated in a diverse, real-world coinfected cohort, despite the use of off-label, less efficacious regimens. High-frequency injection drug use and cirrhosis were associated with an increased risk of failure.

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.

AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C

Clinical Liver DiseaseVolume 12, Issue 5 p. 117-117 IntroductionFree Access AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C First published: 14 December 2018 https://doi.org/10.1002/cld.791Citations: 18AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Watch a video presentation of this article Watch the interview with the author The landscape of treatment for hepatitis C virus (HCV) infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies in 2011. The pace of change has increased rapidly as numerous new drugs with different mechanisms of action have become available over the past few years. To provide healthcare professionals with timely guidance as new therapies become available and are integrated into HCV regimens, the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD), developed a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations for hepatitis C management. The AASLD/IDSA guidance on hepatitis C addresses management issues ranging from testing and linkage to care, the crucial first steps toward improving health outcomes for HCV-infected persons, to the optimal treatment regimen in particular patient situations. Recommendations are evidence based and rapidly updated as new data from peer-reviewed research become available. For each treatment option, recommendations reflect the best possible management for a given patient and a given point of disease progression. Recommendations are rated with regard to the level of the evidence and strength of the recommendation. The AASLD/IDSA guidance on hepatitis C is supported by the membership-based societies and not by pharmaceutical companies or other commercial interests. The governing boards of AASLD and IDSA have appointed an oversight committee of 4 co-chairs and selected panel members from the societies. This guidance should be considered a living document in that the recommendations are updated frequently as new information and treatments become available. Please listen to Dr Ray Chung discuss the most recent AASLD/IDSA HCV guideline update.1 Reference 1 AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org Citing Literature Volume12, Issue5November 2018Pages 117-117 ReferencesRelatedInformation

Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection.

Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear. We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy. Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule". SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.

Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration's evaluation.

On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) fixed-dose combination (FDC), an interferon-free, complete regimen for adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing a nonstructural protein 5A (NS5A) inhibitor; and • genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Approval was based on an acceptable safety profile and high sustained virological response rates 12 weeks after the end of treatment (SVR12) in two phase 3 clinical trials in subjects previously treated with a direct-acting antiviral (DAA) regimen. In POLARIS-1, 96% of SOF/VEL/VOX-treated subjects achieved SVR12. In POLARIS-4, 98% of SOF/VEL/VOX-treated subjects achieved SVR12. A key and challenging question in evaluating the data was determining the contribution of VOX to SOF/VEL and how this differed depending on the genotype and patient population. In this article, we provide our perspective on the issues considered in making these determinations, especially regarding the POLARIS-4 data in subjects who have previously been treated with a chronic HCV regimen containing sofosbuvir without an NS5A inhibitor. Conclusion: We seek to provide context as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6) while the indication for NS5A inhibitor- naïve patients was limited to HCV genotypes 1a and 3 only. (Hepatology 2018;67:482-491).

New therapeutic agents marketed in 2017: Part 2

Abstract Objective To provide information about the most important properties of new FDA-approved therapeutic agents marketed in 2017. Data sources Product labeling supplemented selectively with published studies and drug information reference sources. Data synthesis The first part ( Pharmacy Today, September 2017) of this series reviewed seven new FDA-approved therapeutic agents marketed in 2017. This second part of the series covers nine additional therapeutic agents marketed in 2017: bezlotoxumab, sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir (two new agents in a combination formulation), betrixaban, plecanatide, brodalumab, guselkumab, and sarilumab. The authors review indications, mechanisms of action, and information on dosage and administration for these new agents, as well as their most important pharmacokinetic properties, adverse events, and other risks and precautions. They compare the new agents with older drugs marketed for the same indications and identify the advantages and disadvantages of the new drugs. Conclusion Sofosbuvir/velpatasvir/voxilaprevir, which includes the new antiviral agent voxilaprevir in combination with previously available antiviral agents, is indicated for the treatment of chronic hepatitis C virus (HCV) infection caused by all six HCV genotypes in adults for whom certain previous HCV regimens have failed. Glecaprevir/pibrentasvir, a combination formulation of two new antiviral agents, is the first combination used in an 8-week course of treatment for all six HCV genotypes infections in patients without cirrhosis who have not been previously treated. Bezlotoxumab, a monoclonal antibody that binds to Clostridium difficile toxin B, reduces recurrence of C. difficile infection in patients who are at high risk of recurrence. Betrixaban is the first orally administered anticoagulant to be approved for venous thromboembolism prophylaxis for in-hospital and extended-duration use in acutely ill medical patients. Plecanatide has properties similar to those of linaclotide and is indicated for the treatment of adult patients with chronic idiopathic constipation. Brodalumab and guselkumab are interleukin inhibitors approved for the treatment of adult patients with moderate to severe plaque psoriasis. However, the labeling for brodalumab includes a boxed warning for suicidal ideation and behavior, and it should only be used in patients who have not responded or have lost response to other systemic therapies. Sarilumab, an interleukin-6 inhibitor with properties that are most similar to those of tocilizumab, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.

Research priorities to achieve universal access to hepatitis C prevention, management and direct-acting antiviral treatment among people who inject drugs

Globally, it is estimated that 71.1 million people have chronic hepatitis C virus (HCV) infection, including an estimated 7.5 million people who have recently injected drugs (PWID). There is an additional large, but unquantified, burden among those PWID who have ceased injecting. The incidence of HCV infection among current PWID also remains high in many settings. Morbidity and mortality due to liver disease among PWID with HCV infection continues to increase, despite the advent of well-tolerated, simple interferon-free direct-acting antiviral (DAA) HCV regimens with cure rates >95%. As a result of this important clinical breakthrough, there is potential to reverse the rising burden of advanced liver disease with increased treatment and strive for HCV elimination among PWID. Unfortunately, there are many gaps in knowledge that represent barriers to effective prevention and management of HCV among PWID. The Kirby Institute, UNSW Sydney and the International Network on Hepatitis in Substance Users (INHSU) established an expert round table panel to assess current research gaps and establish future research priorities for the prevention and management of HCV among PWID. This round table consisted of a one-day workshop held on 6 September, 2016, in Oslo, Norway, prior to the International Symposium on Hepatitis in Substance Users (INHSU 2016). International experts in drug and alcohol, infectious diseases, and hepatology were brought together to discuss the available scientific evidence, gaps in research, and develop research priorities. Topics for discussion included the epidemiology of injecting drug use, HCV, and HIV among PWID, HCV prevention, HCV testing, linkage to HCV care and treatment, DAA treatment for HCV infection, and reinfection following successful treatment. This paper highlights the outcomes of the roundtable discussion focused on future research priorities for enhancing HCV prevention, testing, linkage to care and DAA treatment for PWID as we strive for global elimination of HCV infection.