Hepatitis C Virus Direct-acting Antiviral Agents Research Articles

Low Utilization of Direct-Acting Antiviral Agents in a Large National Cohort of HIV and HCV Coinfected Medicare Patients in the United States: Implications for HCV Elimination.

Hepatitis C virus (HCV) infection is common in people living with HIV/AIDS (PLWHA). The advent of direct-acting antiviral agents (DAAs) has made HCV elimination a realistic goal. We conducted a retrospective cohort study using the US Medicare Fee-For-Service claims data and outpatient prescription drug data to assess the HCV DAA initiation and completion among newly diagnosed HIV-HCV-coinfected Medicare patients enrolled in 2014-2016. DAA initiation was defined as filling at least 1 prescription of DAAs during 2014-2016. DAA completion was defined as taking an 8-week or longer DAA treatment course for patients without cirrhosis and a 12-week or longer treatment duration for those with cirrhosis. Among 12 152 HIV-HCV-coinfected Medicare patients, 20.9% received the DAA treatment in 2014-2016. The average time from HCV diagnosis to DAA initiation was 277 days. The overall DAA completion rate was 92% among 2537 patients who used DAAs. Interventions are needed to improve DAA uptake in PLWHA.

Treatment of HCV Infection with Direct-Acting Antiviral Agents in Patients with HIV/HCV Co-Infection: A Systematic Review

Context: Hepatitis C virus (HCV) infection is a significant cause of chronic liver disease in patients with human immunodeficiency virus (HIV) infection. Introduction of HCV direct-acting antiviral agents (DAAs) revolutionized the treatment of hepatitis C in patients with HIV/HCV co-infection. In this study, we systematically reviewed the treatment of chronic HCV infection in patients with HIV/HCV co-infection. Evidence Acquisition: In this systematic review, electronic databases including PubMed, Scopus, ScienceDirect, and Web of Science were comprehensively searched using appropriate strategies containing all related keywords of “HCV”, “HIV” and “DAA”. Studies assessed the effectiveness of interferon-free HCV antiviral therapies in patients with HIV/HCV co-infection were evaluated for inclusion in the systematic review. Results: After the screening of 728 records, we included 33 articles in our study, and seven different HCV antiviral regimens were evaluated. Ten studies for sofosbuvir plus simeprevir (SVR ranged from 72.2% to 100%), eight studies for sofosbuvir plus ribavirin (SVR ranged from 51.6% to 91.6%), 12 studies for sofosbuvir/ledipasvir (SVR ranged from 88.8% to 100%), eight studies for sofosbuvir plus daclatasvir (SVR ranged between 84.6% and 100%), two studies for grazoprevir/elbasvir (SVR ranged from 86.6% to 96.5%), six studies for ombitasvir/paritaprevir/ritonavir plus dasabuvir (SVR ranged from 90.6% to 100%), and just one study for sofosbuvir/velpatasvir with 95.2% SVR rate. Conclusions: This study found that treatment of HCV infection with DAAs can result in high SVR rate in patients with HIV/HCV co-infection.

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.

Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. Descriptive case series. U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). 29 patients with HBV-R receiving HCV DAAs. Clinical and laboratory data. The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection. None.

Is stronger better in curing hepatitis C virus infection?

Thanks to a better understanding of the hepatitis C virus (HCV) life-cycle, HCV direct-acting antiviral agents (DAAs) targeting the viral proteins implicated in the virus replication have been developed: they inhibit specifically the NS3/4A protease, the NS5B polymerase and the multifunctional NS5A replication complex (1). DAAs have revolutionized the treatment of HCV infection over the last 5 years. Oral interferon-free combinations of at least two DAAs showed high antiviral efficacy, easy dosing, fair tolerance, and manageable drug-drug interactions, whatever the combination for treatment duration of 8, 12 or 24 weeks according to the patients profile.

Awareness of the severity of liver disease re-examined using software-combined biomarkers of liver fibrosis and necroinflammatory activity

BackgroundEffective antiviral treatment (direct-acting antiviral agents (DAAs)), the requirement for a fibrosis score to support DDA reimbursement and a screening strategy, such as the USA baby boomer campaign, should lead...

Incidence and Management of Hematological Toxicities Associated with Treatment of Hepatitis C Virus Infection in Cancer Patients

▪BackgroundHematologic toxicity is a common treatment complication of chronic hepatitis C virus (HCV) infection, especially when interferon (IFN) and ribavirin are used. The side effects of treatment are often augmented in cancer patients due to baseline cytopenias. These adverse events often lead to dose reduction or discontinuation of antivirals. Hematopoietic growth factors (GF) and blood transfusions are used to counteract toxicities allowing patients to complete treatment. We aimed to evaluate the incidence and management of hematological toxicity associated with different types of HCV treatment in cancer patients.MethodsMedical records of cancer patients treated for HCV infection at MD Anderson Cancer Center between 2009 and 2014 were reviewed. Those seen from 8/2009 to 10/2012 were analyzed retrospectively, whereas those seen from 11/2012 to 7/2014 were prospectively studied. Patients who received combination treatment with peg-IFN and ribavirin (PR), telaprevir or boceprevir plus PR (TBPR), sofosbuvir plus PR (SPR), sofosbuvir with simeprevir (SS) and sofosbuvir with ribavirin (SR) were included in the study. Data regarding treatment interventions (dose reductions and/or discontinuation of antivirals), use of GFs or blood transfusions in the management hematological side effects were analyzed. Categorical variables were analyzed using the χ2 or Fischer’s exact test.ResultsSixty-five patients were identified (Table). The need for treatment interventions, GFs or blood transfusions was comparable between patients with hematologic malignancies and solid tumors. Seventeen (81%) of the PR group, 13 (93%) of the TBPR group, 6 (67%) of the SPR group, 9 (64%) of the SR group and 0 of the SS group required treatment interventions (p <0.001) (Figure). Twelve (57%) of the PR group, 9 (64%) of the TBPR group, 3 (33%) of the SPR group, 2 (14%) of the SR group and 0 of SS group required the use of GFs (p <0.01). Six (29%) patients of the PR group, 9 (64%) from the TBPR group, 1 (11%) from the SPR group, 1 (7%) from the SR group and 0 from the SS group received blood transfusions (p <0.01). From patients who received GFs (N=26), 2 received epoetin alfa, 11 darbepoetin alfa, 2 filgrastim, 17 pegfilgrastim, 4 eltrombopag and 1 romiplostim. Ten of them (39%) required multiple GFs, with darbepoetin alfa and pegfilgrastim being the most common combination. Combined use of GFs was only needed in those receiving TBPR (56%), PR (33%) or SPR (33%). Overall, 82% of the patients who received treatment interventions, 77% of those who received GFs and 47% of those who received blood transfusions were able to complete HCV treatment. Thirteen patients (62%) from the PR group, 12 (86%) from the TBPR group, 3 (33%) from the SPR group, 2 (14%) from the SR group and 0 from the SS group developed grade 3 or 4 hematologic toxicities (p <0.001). One (25%) of 4 patients receiving eltrombopag developed portal vein thrombosis. No other patients developed side effects attributed to GF support.ConclusionsHematologic toxicity during HCV treatment in cancer patients is common. The use of GFs helps manage such toxicity, allowing completion of antiviral therapy. The newer HCV direct-acting antiviral agents are associated with less hematological toxicity, requiring fewer interventions, GFs and blood transfusions. No hematologic side effects were seen with the IFN-free, ribavirin-free combination of SS.Abstract 4126. TableCharacteristics of HCV-infected cancer patients treated with different antiviral regimensPR (N=21)%TBPR (N=14)%SPR (N=9)%SR (N=14)%SS (N=7)%Age, median (range)54.3 (45-68)59.7 (49-69)54.7 (35-75)62.7 (33-82)60.9 (46-64)Male gender13 (62)6 (43)4 (44)8 (57)4 (57)Type of cancer Solid Hematologic16 (76)5 (24)10 (71)4 (29)4 (44)5 (56)6 (43)8 (57)4 (57)3 (43)Cirrhosis5 (24)7 (50)2 (22)3 (21)6 (86)Baseline labs, median (range) Hemoglobin (g/dL) Platelets (x1,000 K/uL) Absolute Neutrophil count (K/uL)12.8 (10-15.9)165 (83-408)1385 (940-6120)13.5 (9.6-16.3)112 (52-397)2360 (800-4900)13.8 (8.8-14.2)183 (121-268)2680 (1650-5810)13.1 (9.8-15.5)179 (57-390)2490 (1040-4040)13.8 (12.3-16.1)141 (59-239)3000 (1390-5030)FDA-recommended duration of antiviral treatment, weeks24-4824-481212-2412Duration of antiviral treatment, median (range)24 (2-48)19 (3-52)12 (1-12)*12 (3-24)*6 (3-12)**Patients may still be on treatment. [Display omitted] DisclosuresTorres:Genentech,: Consultancy; Vertex Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc. : Consultancy, Research Funding; Gilead Sciences: Consultancy.

Finally sofosbuvir: an oral anti-HCV drug with wide performance capability.

Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance.

Similar prevalence of low-abundance drug-resistant variants in treatment-naive patients with genotype 1a and 1b hepatitis C virus infections as determined by ultradeep pyrosequencing.

Background and ObjectivesHepatitis C virus (HCV) variants that confer resistance to direct-acting-antiviral agents (DAA) have been detected by standard sequencing technology in genotype (G) 1 viruses from DAA-naive patients. It has recently been shown that virological response rates are higher and breakthrough rates are lower in G1b infected patients than in G1a infected patients treated with certain classes of HCV DAAs. It is not known whether this corresponds to a difference in the composition of G1a and G1b HCV quasispecies in regards to the proportion of naturally occurring DAA-resistant variants before treatment.MethodsWe used ultradeep pyrosequencing to determine the prevalence of low-abundance (<25% of the sequence reads) DAA-resistant variants in 191 NS3 and 116 NS5B isolates from 208 DAA-naive G1-infected patients.ResultsA total of 3.5 million high-quality reads of ≥200 nucleotides were generated. The median coverage depth was 4150x and 4470x per NS3 and NS5B amplicon, respectively. Both G1a and G1b populations showed Shannon entropy distributions, with no difference between G1a and G1b in NS3 or NS5B region at the nucleotide level. A higher number of substitutions that confer resistance to protease inhibitors were observed in G1a isolates (mainly at amino acid 80 of the NS3 region). The prevalence of amino acid substitutions that confer resistance to NS5B non-nucleoside inhibitors was similar in G1a and G1b isolates. The NS5B S282T variant, which confers resistance to the polymerase inhibitors mericitabine and sofosbuvir, was not detected in any sample.ConclusionThe quasispecies genetic diversity and prevalence of DAA-resistant variants was similar in G1a and G1b isolates and in both NS3 and NS5B regions, suggesting that this is not a determinant for the higher level of DAA resistance observed across G1a HCV infected patients upon treatment.

Hepatitis C Direct-acting Antiviral Agents

Hepatitis C virus (HCV)-related liver disease is a major source of mortality in HIV-infected patients. Approximately one third of all patients with HIV are co-infected with HCV. Patients co-infected with HIV/HCV have shown lower rates of sustained virologic response with pegylated-interferon and weight-based ribavirin as well as more rapid progression of fibrosis than those with HCV mono-infection. Several direct-acting antiviral agents (DAAs), developed originally for HCV mono-infection, are being reevaluated for HIV/HCV co-infection. In addition, entirely new DAAs are being developed, including, interferon-free regimens with fewer side effects, allowing novel treatment opportunities for difficult-to-treat patients. In order for HCV DAAs to be successfully used in the HIV/HCV co-infected population several hurdles must be overcome, including adverse event management and drug-drug interactions. The aim of this review is to discuss the results of trials for new HCV therapies being developed for HIV/HCV co-infected patients and the impact of interferon-free regimens on treatment in the future.

A 96-well based analysis of replicon elimination with the HCV NS5A replication complex inhibitor daclatasvir

A 96-well based replicon elimination and colony formation assay is presented for comparing the resistance barrier of the hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (DCV, BMS-790052) on three HCV genotypes (gts) in a proof of concept experimental protocol. The 96-well assay format provides both individual colony as well as population characterization and is readily applicable to other HCV direct-acting antiviral agents (DAAs). The assay provides an assessment of HCV replication levels over a 5log10 range by measuring a luciferase reporter resident in the HCV replicons. Individual colony status can be measured with a separate and compatible resazurin assay to assess relative host cell fitness following inhibitor treatments. The methods employed are non-toxic and leave intact isolatable colonies that can be used for phenotyping and genotyping. The utility of the assay is demonstrated by the identification and isolation of resistant variants as well as in the ranking of the relative resistance barrier for the replication complex inhibitor DCV for gts 1a, 1b and 2a. The format provides a quantitative ranking based upon luciferase activity and has the ability to monitor DAA resistance development over time for large numbers of compounds.