Hepatitis C Virus Genotype 1a Infection Research Articles

Molecular characterization of the nonstructural 5A (NS5A) region of hepatitis C virus in Thai blood donors.

Direct acting antivirals (DAAs) have been developed for hepatitis C virus (HCV) therapy, and they are usually effective, however resistance to DAA regimens has also been reported to have a significant impact. Resistance associated substitutions (RASs) in the NS5A region are known to be correlated with failure of DAA therapy. HCV genotypes 3a and 1 are the most prevalent genotypes in Thailand. This study analyzed the type and frequency of RASs associated with DAA failure, focusing on the NS5A region. Serum samples of HCV genotype 3a, 1a, and 1b infection from Thai blood donors were selected. The NS5A region was amplified using reverse transcription-polymerase chain reaction (RT-PCR). A phylogenetic tree was constructed to identify the genotypes of HCV. Nucleotide sequencing and amino acid sequencing were conducted to determine the prevalence of RASs. Construction of the phylogenetic tree indicated that 29 samples were genotype 3a, 11 samples were genotype 1a, and 9 were genotype 1b. Both HCV genotypes 1a and 3a can be categorized into two subclades. Results showed that the NS5A substitutions A30V/K, A62T/V/I/M/P/S/L, and S98G were present in HCV genotype 3a. In HCV genotype 1a, only NS5A RASs H54Y was detected. NS5A amino acid substitutions Q54H and P58L were found in HCV genotype 1b. In conclusion, NS5A RASs at amino acid positions 30, 62, 54, 58, and 98 are present within HCV genotypes 3a and 1. While keeping in mind that additional information was not available on the anonymous blood donors tested in this study, these findings can contribute to understand the NS5A mutation. Further study with known patients under drug treatment is recommended.

High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway

Background and aims The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. Method This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). Results We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22–73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. Conclusion We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Diversity of the hepatitis C virus NS5B gene during HIV co-infection.

Viral diversity is an important feature of hepatitis C virus (HCV) infection and an important predictor of disease progression and treatment response. HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes, although limited data are available regarding the impact of HIV on non-structural genes of HCV, particularly in the absence of direct-acting therapies. The genetic diversity and presence of drug resistance mutations within the RNA-dependent RNA polymerase (NS5B) gene were examined in 3 groups of women with HCV genotype 1a infection, including those with HCV mono-infection, antiretroviral (ART)-naïve women with HIV/HCV co-infection and CD4 cell count <350 cells/mm3, and ART-naïve women with HIV/HCV co-infection and CD4 cell count ≥350 cells/mm3. None had ever been treated for HCV infection. There was evidence of significant diversity across the entire NS5B gene in all women. There were several nucleotides and amino acids with distinct distributions across the three study groups, although no obvious clustering of NS5B sequences was observed based on HIV co-infection or CD4 cell count. Polymorphisms at amino acid positions associated with resistance to dasabuvir and sofosbuvir were limited, although the Q309R variant associated with ribavirin resistance was present in 12 individuals with HCV mono-infection, 8 HIV/HCV co-infected individuals with CD4 <350 cells/mm3, and 12 HIV/HCV co-infected individuals with CD4 ≥350 cells/mm3. Previously reported fitness altering mutations were rare. CD8+ T cell responses against the human leukocyte antigen (HLA) B57-restricted epitopes NS5B2629-2637 and NS5B2936-2944 are critical for HCV control and were completely conserved in 44 (51.8%) and 70 (82.4%) study participants. These data demonstrate extensive variation across the NS5B gene. Genotypic variation may have a profound impact on HCV replication and pathogenesis and deserves careful evaluation.

ERAP1 allotypes shape the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection

Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. We performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury. Two hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV. ERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.

Personalized treatment of hepatitis C genotype 1a in Norway and Sweden 2014–2016: a study of treatment outcome in patients with or without resistance-based DAA-therapy

Objectives: Resistance-associated substitutions (RASs) may impair treatment response to direct-acting antivirals (DAA) in hepatitis C virus (HCV) treatment. We investigated the effects of baseline NS3-RASs (Q80K and R155K) and clinically relevant NS5A-RASs in patients with HCV genotype (GT) 1a infection on treatment outcome, with or without resistance-based DAA-treatment. This multi-center study was carried out between 2014 and 2016.Patients/methods: Treatment in the intervention group (n = 92) was tailored to baseline resistance. Detection of NS3-RAS led to an NS5A-inhibitor-based regimen and detection of NS5A-RAS to a protease-inhibitor regimen. Patients without baseline RAS in the intervention group and all patients in the control group (n = 101) received recommended standard DAA-treatment.Results: The sustained virologic response rates (SVR) in the intervention and control groups were 97.8% (90/92) and 93.1% (94/101), respectively (p = .174). A trend toward higher SVR-rate in cirrhotic patients (p = .058) was noticed in the intervention group compared to the control group with SVR-rates 97.5% (39/40) and 83.3% (35/42), respectively. All patients with baseline NS3 (Q80K/R155K) or NS5A-RASs in the intervention group achieved SVR with personalized resistance-based treatment. In the control group, five patients with Q80K or R155K at baseline were treated with simeprevir + sofosbuvir and treatment failed in two of them. Furthermore, one of three patients who failed ledipasvir + sofosbuvir treatment had NS5A-RASs at baseline.Conclusions: In line with the findings of the OPTIMIST-2 trial for Q80K and the EASL-guidelines 2016 for NS5A-RASs, baseline RASs appeared to have an impact on treatment outcome albeit a statistical significance was not observed in this low-prevalence population.

Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1

Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93-99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. Gilead Sciences.

A Case Series of HCV Genotype 1a Infection Patients With HIV Co-infection Treated With 8 Weeks of Ledipasvir-Sofosbuvir

HIV (human immunodeficiency virus) co-infection in hepatitis C virus (HCV) patients increases the risk of liver fibrosis and hepatic decompensation. The current American Association For The Study of Liver Disease (AASLD) guidelines recommend a 12-week course of Ledipasvir-Sofosbuvir for HCV/HIV co-infection. We present a case series of four HCV patients with HIV co-infection treated with 8 weeks of therapy. A total of seventy-seven patients with HCV and HIV co-infection were seen in our clinic between May 2014 to May 2017. Four patients (n=4) with HCV genotype 1a and HIV co-infection were effectively treated with 8 weeks of Ledipasvir-Sofosbuvir. SVR was achieved after initial 4 weeks of therapy, and viral load continued to be undetectable at 8,12,16,24 and 28 weeks post treatment. All patients were African American. Three patients had history of intra-venous drug abuse and one out of three patients was actively using cocaine. One patient was a homosexual male. At the time of initiation of therapy all patients were immune to hepatitis A and B. HCV viral load was below 1 million IU/ml for 3 patients and 3602676 IU/ml for one patient. Fibrosure testing revealed stages F2(n=1) and F3(n=3). All patients were concurrently treated for HIV with antiretroviral therapy including Efavirenz / Emtricitabine / Tenofovir (n=3) and Emtricitabine/Rilpivirine/Tenofovir (n=1). Ledipasvir-sofosbuvir for 8 weeks with intensive monitoring of medication compliance provides a safe and highly effective treatment for patients co-infected with HCV genotype 1a and HIV. A shorter duration of therapy can lead to signficant cost reduction in treatment and improve compliance for particular HCV/HIV co-infected patients. Prospective trials with a large number of patients are needed to identify the type of patients, which might benefit from shorter courses of therapy.

Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study

We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83-12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials

Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis

Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12-18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL. Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevirfor 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infectionscompared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevirand ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. In an analysis of data from 6 clinical trials, rates of SVR12 rangedfrom 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure didnot occur in any treatment-experienced patients when theduration of elbasvir/grazoprevir and ribavirin therapy wasextended to 16 or 18 weeks. Baseline analysis of RASs (orin theabsence of this test, a history of nonresponse to interferon) canbe used to determine treatment duration andthe need for ribavirin in patients with HCV genotype1ainfection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.

Safety and effectiveness of a 12-week course of sofosbuvir and simeprevir ± ribavirin in HCV-infected patients with or without HIV infection: a multicentre observational study

The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals.

Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir

Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n= 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.

Lower SVR Rates in Treatment Experienced Cirrhotic Veterans for Hepatitis C Genotype 1

Introduction: Newer therapies for hepatitis C virus (HCV) genotype 1 produce high rates of sustained virologic response (SVR) in the general population. Not known is whether these therapies translate to a veteran population, with high HCV prevalence, and pleomorphic epidemiological environments such as alcohol, tobacco, obesity, homelessness, and substance abuse. This study assessed the SVR in such a population. Methods: A retrospective study was performed on all patients treated for HCV genotype 1 infection during the 2015 federal fiscal year at VA Loma Linda Health Care System (VALLHCS). Patients received 8, 12, or 24 weeks of daily therapy with ledipasvir-sofosbuvir (LDV/SOF) or ombitasvir-paritaprevirritonavir with dasabuvir (OPRD) with or without ribavirin (RBV) according to AASLD guidelines. All patients were evaluated for sustained virologic response at 12 weeks (SVR12) by serum quantitative PCR. Results: Ninety-seven patients were reviewed of which 55% received LDV/SOF, and 45% received OPRD therapy. Demographic analysis revealed that ninty-eight percent of patients were male, mean age 62, of which 25% were black, and 11% were Hispanic. Sixty-one percent had cirrhosis, 35% were treatment experienced, and 75% had HCV genotype 1a infection. All patients achieved virologic response during therapy, reaching an undetectable viral load by PCR. SVR12 was achieved in 93% of all patients (95% confidence interval [CI], 86-96). SVR12 was achieved in 100% of non-cirrhotic patients who received LDV/SOF+/-RBV (95% CI, 85-100), 94% of non-cirrhotic patients who received OPRD+/-RBV (95% CI, 72-99), 84% of cirrhotic patients who received LDV/SOF+/-RBV (95% CI, 67-93), and 96% of cirrhotic patients who received OPRD (95% CI, 82-99). The lowest SVR12 rate of 71% was observed in the treatment-experienced cirrhosis group who received LDV/SOF+RBV. The most common adverse effects included fatigue, headache, insomnia, and nausea.Figure 1Conclusion: New oral therapies for chronic HCV genotype 1 infections are effective in VA healthcare system patients with SVR12 rates comparable to the general population, except in treatment experienced cirrhotics. This group achieved a lower SVR12. Factors contributing may be the pleomorphic demographics of the VA population, which is pending further analysis.

Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response

The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure. We collected data from 2099 participants in the HCV-TARGET study with complete virologic data (per-protocol population). We analyzed data from 1788 patients receiving ledipasvir-sofosbuvir (282 for 8 weeks, 910 for 12 weeks, 510 for 24 weeks, and 86 for a different duration) and 311 receiving ledipasvir-sofosbuvir plus ribavirin (212 for 12 weeks and 81 for 24 weeks, 18 for other duration) to estimate SVR12 (with 95% confidence interval [CI]), and logistic regression methods to identify factors that predicted an SVR12. The overall study population was 25% black, 66% with HCV genotype 1A infection, 41% with cirrhosis, 50% treatment-experienced, and 30% receiving proton pump inhibitors at start of treatment. In the per-protocol population, SVR12s were achieved by 96% of patients receiving ledipasvir-sofosbuvir for 8 weeks (95% CI, 93%-98%), 97% receiving the drugs for 12 weeks (95% CI, 96%-98%), and 95% receiving the drugs for 24 weeks (95% CI, 93%-97%). Among patients also receiving ribavirin, SVR12 was achieved by 97% of the patients receiving the drugs for 12 weeks (95% CI, 94%-99%) and 95% receiving the drugs for 24 weeks (95% CI, 88%-99%). Of the 586 patients who qualified for 8 weeks of treatment, only 255 (44%) received the drugs for 8 weeks. The rate of SVR12 among those who qualified for and received 8 weeks of therapy was similar in those who qualified for 8 weeks but received 12weeks therapy (96%; 95% CI, 92%-99% vs 98%; 95% CI,95%-99%). Factors that predicted SVR12 were higher albumin (≥3.5 g/dL), lower total bilirubin (≤1.2 g/dL), absence of cirrhosis, and absence of proton pump inhibitor use. Regimens containing ledipasvir and sofosbuvir are highly effective for a broad spectrum of patients with HCV genotype 1 infection treated in different clinical practice settings. Expanded use of 8-week treatment regimens for eligible patients is supported by these real-world results. Modification of proton pump inhibitor use may increase rates of SVR. ClinicalTrials.gov no. NCT01474811.

Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C Virus Infection.

The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34–70 years), median creatinine of 1.2 mg/dL (0.66–1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in post-kidney transplant patients with chronic HCV infection.

Prevalence of Resistance-Associated Substitutions in HCV NS5A, NS5B, or NS3 and Outcomes of Treatment With Ledipasvir and Sofosbuvir

We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/sofosbuvir for 8 weeks (P= .011), but not for 12weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sofosbuvir (P< .001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or L320S) and all achieved an SVR12. Of patients previously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12. Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. Merck Sharp & Dohme Corp.

Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir: A Review in Chronic HCV Genotype 1 Infection.

A fixed-dose tablet comprising ombitasvir (an NS5A replication complex inhibitor), paritaprevir (an NS3/4A protease inhibitor) and ritonavir (a cytochrome P450 inhibitor) taken in combination with dasabuvir (an NS5B polymerase inhibitor) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in several countries, including the USA (copackaged as Viekira Pak(™)) and those of the EU (Viekirax(®) and Exviera(®)). In phase II and III trials, this interferon-free regimen, taken±ribavirin, provided high rates of sustained virological response 12weeks post-treatment in adults with chronic HCV genotype 1a or 1b infection, including those with compensated cirrhosis, liver transplants or HIV-1 co-infection. The regimen was generally well tolerated, with nausea, insomnia, asthenia, pruritus, other skin reactions and fatigue being among the most common tolerability issues. Thus, ombitasvir/paritaprevir/ritonavir plus dasabuvir is an effective interferon-free, direct-acting antiviral regimen for use±ribavirin in a broad range of adults chronically infected with HCV genotype 1.

Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection.

To review the data with ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Phase I, II, and III trials and review articles were identified through MEDLINE (1996-January 2015) and PubMed (1996-January 2015), conference abstracts, and US national clinical trials registry, using the keywords NS3/4A protease inhibitor, NS5A inhibitor, NS5B polymerase inhibitor, ABT-450, ABT-267, ABT-333, paritaprevir, ombitasvir, and dasabuvir. Preclinical, phase I, II, and III studies describing pharmacology, pharmacokinetics, efficacy, safety, and tolerability were identified. Noncirrhotic patients with HCV genotype 1b experienced sustained virological response 12 weeks after completion of therapy (SVR12) rates of 96% to 100% when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered for 12 weeks, regardless of inclusion of ribavirin. SVR12 rates of 95% to 97% were seen in noncirrhotic patients with HCV genotype 1a infection who received ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 weeks. Patients with Child-Pugh Class A cirrhosis also experienced high SVR12 rates (91.8%) when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered with ribavirin for 12 weeks. Cirrhotic patients with HCV genotype 1a and a history of prior null response to peginterferon/ribavirin have higher SVR12 rates when ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin are administered for 24 instead of 12 weeks (94.2% vs 88.6%). Adverse events are typically mild, most commonly consisting of fatigue, headache, nausea, and diarrhea. The regimen consisting of ombitasvir/paritaprevir/ritonavir and dasabuvir is highly efficacious in the treatment of HCV genotype 1 infection, with minimal adverse events. It is expected to play an important role in the armamentarium of novel agents that have a high chance of curing HCV infection.

The Combination of Simeprevir and Sofosbuvir Is More Effective Than That of Peginterferon, Ribavirin, and Sofosbuvir for Patients With Hepatitis C–Related Child's Class A Cirrhosis

The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615.