DAA Therapy Research Articles

The Impact of Hepatitis C Virus (HCV) Treatment with Direct-Acting (DAA) on the Incidence of Hepatocellular Carcinoma (HCC) in Patients with Advanced Liver Disease

Background Use DAA has resulted in widespread eradication of Hepatitis C virus (HCV) infection in patients with advanced liver disease (ALD) compared with interferon (IFN)-based treatment era therapy. Recent reports have indicated an increased risk of hepatocellular carcinoma (HCC) associated with HCV treatment with DAA and/or after achieving sustained virologic response (SVR). Decreasing incidence of HCC has been reported for patients treated with IFN-based therapy who achieve SVR. Widespread HCV treatment with IFN-based therapy was started in 2006 at a single center. An interest exist whether there was an increase in HCC incidence after introduction of DAA therapy.Methods A single-center retrospective analysis of HCC incidence from 2009 to 2016 was conducted. Patients with HCC due to non-HCV-related diseases were included as unmatched controls. HCC cases were reviewed for HCV diagnosis, liver disease stage and evidence of prior HCV treatment. HCC rate was calculated using number of at risk patients with ALD who received HCV treatment each calendar year. Descriptive statistics were utilized for trend analysis. A total of 143 cases of HCC was identified between 2009 and 2016 with 110 cases of HCC in HCV patients. 727 at risk patients with ALD received treatment with antiviral therapy.ResultsThere was a progressive decrease in the number of incident HCC in HCV patients. The incidence rate of HCC in HCV patients declined from 23.1% in 2009 to 1.79% in 2016 in at risk patients receiving antiviral therapy. The HCC incidence rates in 2009, 2010, 2011, 2012, 2013, 2014, 2015, and 2016 was 23.1%, 14.3%, 60.0%, 22.2%, 6.25%, 1.48%, 1.11%, and 1.79% respectively. The number of HCC cases in non-HCV patients remain unchanged during the same period. One year HCC survival ranged from 75% to 90% in HCV patients and 38 to 100% in non-HCV patients with no trends in survival identified.Conclusion The incidence of HCC decreased in at risk HCV patients with ALD who received antiviral therapy with the largest decline occurring in patients who received DAA therapy. One year survival did not appear to change during the study period.Disclosures All authors: No reported disclosures.

Retreatment of Chronic HCV Infection after Second Generation DAA Failure in Patients in the NJ VA Healthcare System

Background The data on retreatment of patients with second-generation DAA treatment failure is limited. AASLD retreatment guidelines were established but are classified as class IIb/Level C. We analyzed treatment outcomes in NJ VA patients with prior second-generation DAA failure over a period of 1 year.Methods We performed a retrospective health record review of all HCV patients treated between May 1, 2016 and May 1, 2017. HCV genotypes (GT), the presence of cirrhosis and HIV, DAA type, and RAVs post treatment were evaluated in the treatment failure (TF) group, defined as an inability to achieve the sustained virological response 12 weeks post therapy (SVR12). These patients were retreated with a new DAA regimen selected for their individual characteristics, GT and presence of RAVs and retreatment success rates were recorded.ResultsOf 312 HCV patients, 10 failed second-generation DAA therapy during the outlined period. The TF group had 2 patients with HIV, 5 with cirrhosis, 6 with GT 1a, 2 with GT 1b, and 2 with GT 3a. Patients with GT 1a/b were initially treated with Ledipasvir/Sofosbuvir (LDV/SOF) ± Ribavirin (RBV). One patient with GT 3a was treated with LDV/SOF +RBV, and 1 with SOF+RBV. Three patients stopped treatment early due to side effects or non-compliance. Post-treatment resistance panel was available for 7/10 patients with the following detected mutations: Q30H/K/E/R, L31 L/M, Q20Q, M28V, Q80K, Y93A/H. 2/8 GT1a/b patients were re-treated with SOF/Elbasvir(EBR)/Grazoprevir(GZR)/RBV, 2 with SOF/ Velpatasvir (VEL)/RBV, 2 with EBR/GZR+/-RBV, and 2 with Viekira/SOF/RBV. 1 patient with GT 3a was retreated with SOF/Daclatasvir (DAC), 1 with SOF/VEL/RBV. All 10 patients had an undetectable viral load (VL) at the end of treatment. SVR12 has been achieved for all 5 patients that were tested, with the remaining 5 awaiting week 12.Conclusion The HCV second-generation DAA treatment failure rate in patients at the NJ VAHCS over 1 year was 3.2%. Analysis of available data indicates that the presence of RAVs might be the major cause of treatment failure among HCV patients treated with DAAs in NJ VA. Different retreatment regimens were used for a period of 12–24 weeks with 100% undetectable VL at end of treatment.Disclosures All authors: No reported disclosures.

SAT-209 - Drop of FGF19 levels in patients with HCC development following DAA therapy for chronic hepatitis C

SAT-209 - Drop of FGF19 levels in patients with HCC development following DAA therapy for chronic hepatitis C

FRI-231 - Relapse post DAA therapy: are we too focussed on RAV and neglecting ribavirin?

FRI-231 - Relapse post DAA therapy: are we too focussed on RAV and neglecting ribavirin?

SAT-244 - Utilization of DAA therapies ledipasvir/sofosbuvir and sofosbuvir/ velpatasvir in patients with genotype 1 HCV: real-world experience from the TRIO Network

SAT-244 - Utilization of DAA therapies ledipasvir/sofosbuvir and sofosbuvir/ velpatasvir in patients with genotype 1 HCV: real-world experience from the TRIO Network

FRI-214 - Real world outcomes of DAA therapy for chronic hepatitis C virus infection in the HCV Research UK National cohort

FRI-214 - Real world outcomes of DAA therapy for chronic hepatitis C virus infection in the HCV Research UK National cohort

TREATMENTS OF HEPATITIS C VIRUS LIVER CIRRHOSIS WITH PEGYLAT INTERFERON-RIBAVIRIN AND INTERFERON FREE – COMPARATIVE STUDY

The article describes the adverse effects and efficiency of hepatitis C virus liver cirrhosis treatments available through the National Health Insurance Services, on a population of patients hospitalized at Victor Babes Infectious and Tropical Diseases Hospital, from 2012 to 2016. The population of patients was split into two distinct groups, for which we’ve recorded and comparatively analyzed demographic, clinical and paraclinical characteristics in a database. An evident success was recorded, from the point of view of hitting a clinical SVR index, in the DAA therapy group A, 87% percent compared to 2% in group B for the traditional standard therapy of PegInterferon + Ribavirin. Likewise, the number of adverse effects was lower in Group B versus Group A. Some side effects remained specific to the current cirrhosis treatment, which should be closely monitored.

IL-18, CXCL-8 and CXCL-10 plasma levels decrease in patients with chronic Hepatitis C virus infection undergoing DAA therapy

IL-18, CXCL-8 and CXCL-10 plasma levels decrease in patients with chronic Hepatitis C virus infection undergoing DAA therapy

A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy.

SummaryHepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient’s symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis.Learning points:HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.

Clinical experience with dolutegravir/abacavir/lamivudine in HIV–HCV co-infected patients treated with a sofosbuvir-based regimen—safety and efficacy

Background: There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination.Methods: Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy.Results: Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21–59.78 years). The mean age was 59 years (95% CI: 58.21–59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6–100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events.Conclusion: Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

100% Virological Response with 3D Regimen and Significant Short-term Liver Stiffness Improvement in Patients with Recurrent Hepatitis C Following Liver Transplantation

Introduction: Over recent years, interferon-free regimens offer the prospect of treating the high risk patient groups (liver cirrhosis/liver transplant recipients) with high SVR rates across all genotypes. Aim: To present our experience with DAA agents in LT recipients, as well as to compare pre and posttreatment liver stiffness (LS). Methods: Our cohort consisted of 72 patients with recurrent hepatitis C after LT. All patients received associated ribavirin. The 3D regimen was administered 24 weeks. Fibroscan® and Fibromax® were performed in all patients before DAA therapy. At EOT and at time of SVR12 evaluation only Fibroscan was performed. Results: There were analyzed 32 females and 40 males with a mean age of 55.2±7.0 years. Median time since LT was 26.6 months (range 4.6-176.9 months). At baseline 56.4% of patients had severe necroinfl ammation at Fibromax, cirrhosis (F4) was encountered in 34.5% of LT recipients and grade 3 steatosis in 43.6% of transplanted patients. On treatment virologic response was 100%. End of therapy in this cohort of LT patients was 100%. However, at week 2 after beginning of therapy, only 13.9% of LT recipients were HCV RNA undetectable. Undetectable HCV RNA at 4 weeks of therapy was present in 66.7% of patients with recurrent hepatitis C, but at week 8 all patients were HCV RNA undetectable. Viral load positivity at week 4 was not influenced by baseline HCV RNA or stage of fibrosis. Liver stiffness differed statistically significant according to the activity grades (p=0.02) and fibrosis stages (p < 0.0001) at Fibromax. There was a significant improvement in LS between antiviral therapy start and EOT: 11.9±1.8kPa vs 9.5±1.0kPa (p=0.02) in LT recipients. Conclusion: Conclusions: Virological response was 100% at EOT. LS can reliably assess both inflammation and fibrosis in LT recipients and can be used to follow these patients after HCV eradication. LS significantly decreased after EOT and suggests improvement in liver damage. Data regarding LS at SVR12 will be available at the meeting.

From the Editor’s desk...: October 2016

Oral DAA therapy is a major breakthrough in the treatment of hepatitis C virus (HCV) infection. In this issue of the Journal, two articles raise concerns about this therapy while two other provide relatively good news. In the first of the two “alarming” studies, Reig et al. show an unexpected early tumor recurrence in patients with HCV-related hepatocellular carcinoma (HCC) undergoing DAA therapy. HCC recurrence coincides with HCV clearance. In the second study providing bad news, Conti et al. show that in patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumor recurrence, in the short term. In contrast, in a third study, Cheuk Men Cheung et al. find that DAA therapy in patients with decompensated cirrhosis leads to sustained improvement in liver function, with no evidence of increase in HCC development. Finally, The ANRS collaborative study group on hepatocellular carcinoma, by analyzing three distinct prospective cohorts, and a large number of patients, finds no increased risk of HCC recurrence after DAA therapy, in particular in those who underwent curative HCC treatment including liver transplantation. All these studies were performed in European countries. Together these studies indicate that there is an urgent need for large prospective studies, performed in different continents, evaluating the impact of DAA therapy on the risk of HCC, in particular, in patients with HCV-related cirrhosis.

Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors.

ObjectivesIdentifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment.MethodsTwenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted “detected <12IU/ml” or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR.ResultsAccording to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively.ConclusionHCV RNA “not detected” by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.

Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection.

BackgroundRibavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered.MethodsThe impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1–4 infection, including 88 patients with available IL28b genotyping.ResultsMean ribavirin levels varied between 0.68–5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia.ConclusionWhile data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon.

Long-term impact of achieving sustained virologic response(SVR)by IFN-free DAA treatment in patients with advanced liver disease.

Background and aims: IFN-free antiviral treatment with DAAs improves liver function in many patients with cirrhosis already at the end of therapy, however, results of long-term follow-up are not yet known. The aim of this study was to evaluate patients' virological and clinical outcomes at follow-up week 48 after interferon-free DAA therapy.

Comparison of sleep disorders in chronic hepatitis C patients treated with interferon-based therapy and direct acting antivirals using actigraphy.

Our study included 31 patients in group A (Peg-IFN/RBV/SMV combination therapy) and 41 patients in the group B (IFN-free DAA therapy). We prospectively compared the effect of each antiviral treatment regimen on sleep conditions between the two groups adding actigraphy data. Five parameters detected by actigraphy (objective assessment) and scores of the Pittsburgh Sleep Quality Index (subjective assessment, n = 30 [group A] and 35 [group B]) were estimated. The causal effect of each therapy on sleep disturbances was evaluated at baseline and at 4weeks after commencement of therapy. In terms of baseline characteristics, no significant differences between groups were found, except for hepatitis C virus genotype. In group A, sustained virological response 12 rate was 83.9% (26/31), whereas in group B it was 95.1% (39/41). In group A, each score of waking after sleep onset, activity index, wake episodes, and Pittsburgh Sleep Quality Index at 4weeks significantly increased compared to those evaluated at baseline. In group B, scores of all variables except for sleep episodes at 4weeks did not significantly change compared to those at baseline. Interferon-based triple therapy in patients with CHC may cause significant sleep disturbances. Interferon-free DAA therapy is less likely to deteriorate sleep conditions in patients with CHC.

Su1450 Predictors of Clinical Response in Hepatitis C DAA Therapy

Su1450 Predictors of Clinical Response in Hepatitis C DAA Therapy

Su1434 DAA Therapy Results in High SVR Rates Among Immunosuppressed Patients With Chronic Hepatitis C on Chemotherapy

Su1434 DAA Therapy Results in High SVR Rates Among Immunosuppressed Patients With Chronic Hepatitis C on Chemotherapy

Grazoprevir + elbasvir for the treatment of hepatitis C virus infection

ABSTRACTIntroduction: Hepatitis C virus (HCV)-related liver disease is a cause of significant morbidity and mortality worldwide. Currently, direct-acting antiviral drugs (DAAs) are associated with an increased sustained virologic response (SVR) and are the gold standard for treating HCV infection.Areas covered: The new combination of grazoprevir, an inhibitor of HCV NS3/4A, and elbasvir, an inhibitor of HCV NS5A, once daily will be available for the treatment of HCV infection. This combination therapy has a high efficacy in HCV genotype 1 and 4 infections, inducing a SVR up to 95%, even in difficult to treat patients such as cirrhotic, HIV co-infected, or dialysis-dependent patients, and patients with stage 4–5 chronic kidney disease or those who failed previous therapy. The safety of grazoprevir combined with elbasvir is very good and without significant adverse effects in phase 2 or 3 studies. For patients who failed prior DAA therapy, in vitro and in vivo studies showed that the grazoprevir and elbasvir combination is fully active against resistance to NS3/4A protease inhibitors. Resistance to NS5B inhibitors is least susceptible to grazoprevir or elbasvir.Expert opinion: This new combination of gazoprevir with elbasvir offers an opportunity to cure HCV infection with short interferon-free therapy, even in difficult to treat patients.

Impact of DAA therapy on health-related quality of life in liver transplanted patients. Is there a role for ribavirin?

Impact of DAA therapy on health-related quality of life in liver transplanted patients. Is there a role for ribavirin?