Oral DAA Research Articles

Hepatitis C and hepatitis B virus infection in hemodialysis patients after nationwide direct antiviral agents therapy-experience of 10 Romanian HD centers.

End-stage kidney disease patients (ESKD) receiving hemodialysis (HD) are at a greater risk of hepatitis virus (HV) infections due to the invasive nature of the procedures, frequent hospital stays and surgeries, as well as the immune deficiency status of ESKD. This study was to reassess the hepatitis virus infections prevalence in the HD population in Romania after 5years of oral DAAs therapy and assess the impact on HD patients' outcomes in two cohorts (2015 and 2019). We compared ESKD patients treated with HD in 10 HD centers from the historical regions of Romania in 2015 (n = 1401, Mean age 59.7 ± 12.92years) with patients treated in the same centers in 2019 (n = 1698, mean age 61 ± 12.93years). All patients went through HD therapy for more than 90days. The patients from the 2019 cohort were significantly older (p = 0.005), had a longer duration of HD therapy (p < 0.0001), and had more vascular calcifications (p = 0.015); the crude one-year mortality rate did not differ from the 2015 cohort (9.9 vs. 10.7%, p = 0.46). The prevalence of HBV infection did not differ between the cohorts (4.7% vs. 4.8, p = 0.604) but the prevalence of HCV significantly decreased from 2015 to 2019 (16.9 vs. 10.5%, p < 0.0001). After 15years of a nationwide infection prevention program for HV infections and 5years of DAAs treatment in Romania, the prevalence of HBV did not change but HCV infections decreased significantly, however, it still remained high.

Clinical study on the efficacy of hepatitis B vaccination in hepatitis C virus related chronic liver diseases in Egypt

BackgroundChronic hepatitis B (HBV) and C virus (HCV) infections represent significant public health issues internationally. HBV vaccination has high sero-conversion rates in patients with mild to moderate chronic liver disease but has reduced efficacy in advanced stages. Aimto evaluate the efficacy of hepatitis B vaccination in HCV-related chronic liver disease and identify possible factors that may contribute to hypo-responsiveness in those patients. MethodsOur study was a retrospective observational clinical study carried out at the tropical medicine department. It was conducted on 500 individuals (400 chronic HCV patients and 100 healthy controls). Individuals were divided into 5 groups: A (control group), B (cirrhotic patient not receiving treatment), C (chronic hepatitis patients receiving treatment), D (cirrhotic patients receiving treatment), and E (HCC patients receiving treatment). All individuals were subjected for comprehensive history taking, clinical examination, laboratory investigations, and assessment of anti-HBs titer. ResultsThere is an inverse relationship between the level of anti-HBs Abs and the duration of vaccine. Diabetes and presence of cirrhosis have statistically significant relationship with serum anti-HBs Abs titer (P = 0.007). Oral DAAs therapy is associated with reduced response to HBV vaccine (only 31.75% of the patients were protected). ConclusionHCV infection and its complications significantly impair HBV vaccine response. Levels of anti-HBs Abs decline progressively with increasing duration from the last dose in immunization schedule of HBV vaccine. Diabetes and presence of cirrhosis being the main risk factors for vaccine hypo-responsiveness, also oral DAAs therapy is associated with reduced response to HBV vaccine.

831. Hepatitis C Virus Micro-elimination Within a Human Immunodeficiency Virus Clinic: Challenges in the Home Stretch

BackgroundHepatitis c virus (HCV) eradication among persons with HIV (PWH) is alluring since DAAs efficacy is high regardless of HIV status and PWH in care are usually screened for HCV. Despite the potential, barriers to care have prevented many from achieving sustained virologic response (SVR). We performed a pharmacist-led campaign to reduce the proportion of PWH with active HCV and describe the barriers to care. MethodsThis retrospective review evaluated patients receiving care at a Ryan White-funded clinic from 07/2018 to 12/2020. Patients were eligible if HCV diagnosed ≥1 year and receiving HIV care. The primary endpoint was to compare the prevalence HCV before and after a pharmacy initiative to target the remaining patients at the clinic not treated during first 3 ½ year period of oral DAA therapy availability. Secondary analysis was to identify barriers to care, measure the proportion of patients in each step of the HCV care cascade, and determine predictors of SVR. Among barriers to care, inconsistent engagement was defined as patients with habitual missed appointments. Logistic regression and Chi-square tests were performed.Results46 of 1,100 PWH had active HCV for ≥1 year. Median age, years since HIV and HCV diagnoses were 58.5 years of age, 17 years, and 11.5 years, respectively. Most patients were male (70%), Black (61%), Latinx (28%), HCV genotype 1 (90%), had an HIV RNA < 200 copies/mL (72%), & had Medicaid (87%). 32/46 patients agreed to therapy, with all getting insurance approval and DAAs delivered. Glecaprevir/pibrentasvir (73%) was the preferred by payors, followed by sofosbuvir/velpatasvir (15%). Eight remained with active HCV and 19 achieved SVR. The prevalence rate dropped from 4.2% to 0.7% (P < 0.0001). Active drug use, inconsistent engagement, mental health disorder and nonadherence were initial barriers to care. After multivariate analysis, patients with inconsistent engagement continued to be less likely achieve SVR compared to those we remained consistently in care (aOR: 0.062, 95 CI: 0.009-0.421).HCV care cascade in PWH within a Ryan White-funded clinic Active HCV includes 46 patients with chronic HCV infection receiving HIV in care at clinic, DAA approval process describes patients agreeing to HCV treatment along a continuum of pending laboratory results or pending prior authorization requests, DAA procurement depicts patients that have received approval and delivery of medications, DAA initiation describes patients who started treatment (27 patients), and SVR documented defines patients with an undetectable HCV RNA 12 weeks after therapy (19 patients).ConclusionPharmacists can impact the burden of HCV among PWH receiving care. The HCV care cascade remains tied to the HIV continuum of care, with disengagement from care remaining an important rate-limiting step impeding micro-elimination.Disclosures All Authors: No reported disclosures

Serum microRNA-122 Levels in Egyptian Patients with Chronic Hepatitis C virus Genotype 4 Infection before and after treatment with Direct Acting Antiviral Drugs

Abstract Background Viral hepatitis was estimated to be the 7th leading cause of mortality globally. About half of this mortality is attributed to HCV, a primary cause for liver fibrosis, cirrhosis and cancer. The recent development of highly efficacious oral DAAs provides opportunities for reducing HCV disease burden and its onward transmission, with the potential for eliminating this blood-borne virus as a public health concern. WHO has recently formulated the ‘Global Health Sector Strategy on Viral Hepatitis, 2016– 2021 with service coverage targets to eliminate HCV as a public health threat by 2030. Objective To asses the possible relation of miRNA 122 to HCC development after HCV therapy with direct antiviral drug. Patients and Methods Previous studies suspect that HCV therapy by DAAS may increase risk of HCC so the aim of our study is to evaluate miR-122level at end of HCV treatment by DAAS and compare the results with miR-122level in HCC patients. The study was performed as a case control study in Ain Shams University hospital and Suez Canal authority hospital (Outpatient Clinic), at Ismailia Egypt in the period between Augusts to October 2018. Results These results revealed an effect of treatment by DAAs in HCV infected patients leading to miRNA 122 reduction and this may be related to hepatocarcinogenesis. However, further studies on a large patients number are needed to clarify this point and determine the diagnostic and possible therapeutic value of miRNA 122 in HCV infected patients. Conclusion Baseline MiR-122 level at cutoff value ≤0.26 was significantly lower in HCC patients than chronic HCV patients and normal controls, with a sensitivity of 80%, a specificity of 70%. MiR-122 was significantly reduced at end of HCV therapy with DAAs and became similar to values in HCC patients. Whether this observed reduction is mechanistically related to hepatocarcinogenesis is still a possibility, to be clarified in furtur large scale studies. The reduction of MiR-122 at the end of HCV therapy with DAAs was significantly observed in (F3,F4) patients than those with early fibrosis stages(F1,F2).This again gives a possible explanation of HCC development in HCV patients with advanced fibrosis(cirrhosis)and raises the question about the diagnostic and therapeutic value of miRNA 122 (and possibly other miRNAs)in the management strategy of HCV infected patients.

Effect of hepatitis C eradication with DAA on type II diabetes mellitus control as regard insulin resistance & lipid profile

Abstract Background Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. The patients with chronic HCV infection can have fatty liver, hypobetalipoproteinemia, and hypercholesterolemia that may cause lipid and lipid protein metabolism disorders. Objective To determine the effect of HCV eradication (SVR 12) on type II Diabetic patients as regard insulin resistance &amp; lipid profile. Patients and Methods This study was conducted at the gastroenterology and hepatology unit, Ain shams university hospital and Ahmed Maher teaching hospital, Written informed consent was obtained from all subjects before participating in this study. 100 Egyptian patients with chronic hepatitis C and type II Diabetes mellitus were recruited and received (sofosbuvir &amp; daclatasvir) for 3 months. patients continue on same antidiabetics all over the study. Results The data from the present study provide evidence of an improvement in IR after clearance of HCV by oral DAA regimen. On the basis of these data, it is possible to hypothesize that HCV clearance by DAAs improving IR and reducing stress on beta-cell function prevents or delay the development of type 2 diabetes mellitus and/or metabolic syndrome in chronic HCV infected patients. Conclusion The overall data of this study show that glycemic control improves in patients with diabetes after DAA induced SVR. Patients not only have an improvement in HbA1c level after achieving SVR, they are also less likely to require insulin. the viral clearance due to DAA also led to an improvement of glucose metabolism associated with a global worsening of lipid profile. The HCV clearance by DAA treatment reverses or improves IR and reduces stress on beta-cell function by emphasizing the role of HCV in the development of IR and that this result can prevent IR-related pathological conditions such as worsening liver fibrosis, development of type 2 diabetes, metabolic syndrome and cardio-vascular disorders.

Portal Hypertension Assessment Spleen using Stiffness Measurements after Successful DAAs Therapy in Chronic-HCV Patients

Background: The emergence of noninvasive tests coupled with oral combined DAAs has shifted the paradigm in HCV management. Up to date, it is still questioned if SVR reverse portal hypertension and liver cirrhosis after being treated with direct antiviral therapy. Aim of the work: To investigate the applicability of using splenic stiffness measurements as indicators of portal hypertension improvement after SVR in patients treated with DAAs. Methods: This was a prospective study that included 100 HCV patients from Al-Azhar university hospital who achieved SVR after being treated with DAAs. Liver and spleen stiffness measurements as well as biochemical, virologic and clinical data were assessed at baseline (BL), at end of treatment (EOT), 12 weeks post-treatment, and 24 weeks post-treatment. We used Shear wave elastography (SWE) using ultrasound device Aplio 500 system (Toshiba, japan) to assess splenic stiffness. Results: In our cohort, Spleen stiffness measurements decrease in 58% of the patients. It significantly improved between BL 30.6 kpa (26.3 - 34.8 kPa) and EOT 30.3 kPa (26.2- 34.6 kPa); (P< 0.001), and between BL and 24 weeks post-treatment 30 (26-34.4) kPa. Regarding platelets count, it also improved between BL 205 × 109/L (170- 251 × 109/L) and 24 weeks 218 × 109/L (187- 265 × 109/L) ); (P< 0.001). Conclusions: NITs, especially SSM, decrease significantly after SVR in patients treated with DAAs. So that, they can be used as a mirror to reflect changes in portal hypertension status during following-up period instead of other available invasive methods which is well-known for their complications.

Impact of Treatment with Direct Acting Antiviral Drugs on Glycemic Control in Patients with Hepatitis C and Diabetes Mellitus.

Aim To assess the effect of treating chronic hepatitis C virus (HCV) infection with direct acting antiviral drugs (DAAs) on glycemic control in patients with concomitant diabetes mellitus (DM). Methods We performed a retrospective case-control study in a viral hepatitis ambulatory clinic in Shreveport, Louisiana, during the period 11/01/2014 to 12/31/2017. All the clinic patient ages 18 years and above with treatment-naïve/biopsy-proven chronic hepatitis C and DM (hemoglobin A1C level ≥ 6.5%) who were eligible for treatment were included in the study. Of 118 such patients, 59 were treated with oral DAAs for 8-12 weeks with the goal of achieving a sustained virologic response (SVR). A control group of 59 patients did not receive treatment for their hepatitis C and was followed in the clinic. Patients in the control group did not receive treatment either due to insurance issues or refusal of hepatitis C treatment. Results Fifty-five of the 59 patients treated with DAAs (93%) achieved a SVR. Six months after treatment completion, their mean ± SEM HbA1C level had decreased by 1.1 ± 0.03% (P < 0.0001). Four of the 59 patients treated with DAAs did not achieve a SVR. Their mean HbA1C 6 months after treatment completion had increased by 0.8 ± 0.2%. Furthermore, there was no improvement in HbA1C levels over time in the untreated group (mean HbA1C increase, 0.2 ± 0.05%; P < 0.0001 vs. the treatment group, which had a mean HbA1C decrease of 0.9 ± 0.2%). Conclusion This controlled study demonstrated that treatment of chronic hepatitis C with DAAs results in statistically significant and meaningful reductions in hemoglobin A1C levels in patients with coexisting diabetic mellitus if a SVR is achieved.

Soluble CD163 as a surrogate marker of fibrosis regression in chronic HCV patients receiving direct antiviral agents

Background: Over 80 million people are infected globally with chronic HCV. It promotes inflammation and, hence. hepato-carcinogenesis. As a result, resolving HCV infection should result in decreased incidence of hepatocellular carcinoma. Oral DAAs introduction has changed overall prognosis of HCV. SVR has been linked to improved liver function as well as a reduction in clinical consequences and all-cause mortality. Monocytes and macrophages generate CD163, a hemoglobin scavenger receptor. In a variety of hepatic and viral disorders, soluble CD163 is a well-established marker of portal hypertension and disease severity. In addition, in chronic HCV infection there have been strong connections between macrophage activation, histological inflammation and fibrosis. Our goal is to assess the role of soluble CD163 as a surrogate marker for detection of fibrosis regression in HCV patients treated with direct antiviral agents. Results: Forty chronic HCV patients and ten healthy subjects were included in this study. Serum sCD163 was tested before and 12 weeks after treatment by DAAs. Mean values of sCD163 were statistically significantly higher in chronic HCV case group in comparison to control group, and they showed statistically significant decline after achievement of SVR12 weeks with p value of 6.2 ng/ml with 87.50% sensitivity, 95.83% specificity, with overall accuracy of 97.2%. Conclusion: sCD163 serum level declines with successful DAA therapy and is associated with regression in staging of fibrosis supporting its promising role in monitoring treatment response rather than other methods of fibrosis measurement.

The Real-World Safety and Efficacy of Directly Acting Antiviral Therapy for the Treatment of Patients with Hepatitis C Infection and Decompensated Cirrhosis

AbstractBackground: HCV was considered a major health problem worldwide before the discovery of direct acting antiviral therapy. Patients with chronic HCV and decompensated cirrhosis are not uncommon and represent the greatest thera-peutic challenge.Aim of Study: The primary aim of this study is to assess safety, efficacy and tolerability of all oral DAAs in the treatment of a group of difficult-to-treat population (HCV genotype 4-related decompensated cirrhosis).Patients and Methods: Forty (40) patients with chronic HCV infection and decompensated cirrhosis received different combinations of direct acting antivirals in the form of of sofosbuvir-daclatasvir and sofosbuvir-ledipasvir ± ribavirin for 24wks (for the regimens not containing ribavirin) and 12wks (for the regimens containing ribavirin).All patients in this study were subjected to: History taking regarding demographic data and risk factors predisposing them to HCV infection, full clinical examination, laboratory investigations (CBC, liver functions, PT and INR), CTP scoring before treatment and 12wks after the end of treatment (SVR).Results: Thirty (30) patients complete the duration of treatment and developed Sustained Virological Response (SVR) and those patients showed a significant improvement clinically regarding amount of ascites (p=<0.01), in laboratory findings regarding platelets count (p=<0.05), liver transami-nases (p=Conclusion: Direct acting antivirals are highly effective and showed great improvement in patients with chronic hepatitis C and decompensated cirrhosis clinically and in laboratory findings.

High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar.

Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real-world setting: (a) daclatasvir/sofosbuvir (DCV/SOF)±ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF±RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF±RBV for 12/24weeks (genotype 3: n=193, genotype 6: n=89) and 211 were treated with VEL/SOF±RBV for 12/24weeks (genotype 3: n=83, genotype 6: n=77). Overall SVR rates were high for both DCV/SOF±RBV (96.1%, n=299/311) and VEL/SOF±RBV (95.3%, n=201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n=276) and 6 (n=166; n=127 unique subtype of 6c-l), high SVR rates of 94.9% (n=262/276) and 95.2% (n=158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF±RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.

Evaluation of pharmaceutical intervention in direct-acting antiviral agents for hepatitis C virus infected patients in an ambulatory setting: a retrospective analysis

BackgroundDirect-acting antivirals (DAAs) are known to improve tolerability and have higher efficacy and shorter treatment durations compared with conventional interferon (IFN)-based treatments for hepatitis C virus (HCV) infection. Management of drug interactions and maintenance of patient adherence are important to achieve adequate therapeutic effects, sustained virological response (SVR). In order to maximize the benefits of oral DAA therapy, we established an ambulatory care pharmacy practice, a model of integrated collaboration between physicians and pharmacists, for patients receiving IFN-free DAA therapy. In this study, we evaluated pharmaceutical intervention for patients visiting the ambulatory care pharmacy practice.MethodsHCV-infected outpatients who visited our ambulatory care pharmacy practice between September 2014 and May 2017 were eligible for inclusion in the study. When IFN-free DAAs were first prescribed, the physicians recommended all patients to visit the ambulatory care pharmacy practice after their clinical examination. Subsequently, at the second visit or later, the patients visited the pharmacy service before the physician’s examination. The primary endpoint was SVR, defined as HCV RNA below the lower limit of quantification after the completion of treatment. We also evaluated the adherence rate to DAAs, suggestions to the physicians by the pharmacists, and questions from the patients. All data were obtained retrospectively using an electronic medical record system.ResultsAmong the 401 study subjects, 386 patients completed the IFN-free DAA therapy. A total of 365 patients have reached 12 or 24 weeks after completing the treatment. The overall SVR rate was 98.1% (358/365). The proportion of patients with adherence ≥90% was 99.3% (398/401). Two-hundred and sixty-seven (84%) among 318 suggestions of prescription made by the pharmacists mainly to manage the adverse events were accepted by the physicians. The pharmacists received and answered 1072 questions on DAA therapy from the patients.ConclusionsThis study indicates that the pharmaceutical intervention may contribute to enhanced adherence to DAAs and higher SVR rates in comparison with previous reports. This study also demonstrates that collaboration between physicians and pharmacists in an ambulatory setting provides favorable outcomes for patients receiving IFN-free DAAs.

Baseline NS5A resistance associated substitutions may impair DAA response in real‐world hepatitis C patients

Oral DAA have demonstrated high efficacy as treatment of hepatitis C. However, the presence of resistance-associated substitutions (RAS) at baseline has occasionally been associated with impaired treatment response. Herein, we examined the impact of baseline RAS at the HCV NS5A gene region on treatment response in a real-life setting. All hepatitis C patients treated with DAA including NS5A inhibitors at our institution were retrospectively examined. The virus NS5A gene was analyzed using population sequencing at baseline and after 24 weeks of completing therapy in all patients that failed. All changes recorded at positions 28, 29, 30, 31, 32, 58, 62, 92, and 93 were considered. A total of 166 patients were analyzed. HCV genotypes were as follows: G1a (31.9%), G1b (48.2%), G3 (10.2%), and G4 (9.6%). Overall, 69 (41.6%) patients were coinfected with HIV and 46.7% had advanced liver fibrosis (Metavir F3-F4). Sixty (36.1%) patients had at least one RAS at baseline, including M28A/G/T (5), Q30X (12), L31I/F/M/V (6), T58P/S (25), Q/E62D (1), A92 K (7), and Y93C/H (15). Overall, 4.8% had two or more RAS, being more frequent in G4 (12.5%) followed by G1b (6.3%) and G1a (1.9%). Of 10 (6%) patients that failed DAA therapy, five had baseline NS5A RAS. No association was found for specific baseline RAS, although changes at position 30 were more frequent in failures than cures (22.2% vs 6.4%, P = 0.074). Moreover, the presence of two or more RAS at baseline was more frequent in failures (HR: 7.2; P = 0.029). Upon failure, six patients showed emerging RAS, including Q30C/H/R (3), L31M (1), and Y93C/H (2). Baseline NS5A RAS are frequently seen in DAA-naïve HCV patients. Two or more baseline NS5A RAS were found in nearly 5% and were significantly associated to DAA failure. Therefore, baseline NS5A testing should be considered when HCV treatment is planned with NS5A inhibitors.

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.

Hepatitis C Disease Burden in the United States in the era of oral direct-acting antivirals.

HCV-associated disease burden will still remain substantial in the era of oral DAAs. Increasing HCV screening and treatment capacity is essential to further decreasing HCV burden in the United States. (Hepatology 2016;64:1442-1450).

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure, an expert review

ABSTRACTHepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct – acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA – Dasabuvir, a non – nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven – Johnson syndrome) and strong inducers of CYP3A and CYP2CB.

New Therapies for Hepatitis C Virus.

Hepatitis C virus (HCV), the major etiologic agent of "non-A, non-B hepatitis" was discovered 26 years ago. Even before its discovery, interferon-α (IFN) was already being used for treatment of this infection. The next two decades saw a series of incremental improvements of the IFN therapies by extending the duration of therapy, using IFN in combination with oral ribavirin, using pegylated IFN with ribavirin, and most recently adding oral compounds that inhibit the HCV replication (directly acting antivirals - DAAs) to that regimen. DAAs target multiple steps in the HCV life cycle and are now used in combination to treat HCV infection without the need of IFN. These IFN-free, oral DAAs regimens are highly efficacious, have minimal toxicity and are given for short duration. Approved DAAs can cure more then 90% of persons with chronic HCV infection, thereby reducing the risk of death from cirrhosis and hepatocellular carcinoma. However, these drugs are very expensive, and currently their exorbitant cost significantly restricts the access to this therapy for many HCV infected patients.

Virological Efficacy of New, Oral, Direct-Acting Antivirals in Hepatitis C Patients With Mixed Cryoglobulinemia

Introduction: Mixed cryoglobulinemia (MC), is strongly associated with hepatitis C virus (HCV) infection. Historically, HCV-MC patients are difficult-to-treat. 30-40% patients fail to achieve end of treatment or sustained virological response to combination treatments using pegylated interferon, ribavirin and first generation direct acting antivirals (DAA's). Data on the efficacy of new oral DAA's in this special population is limited. Our study aim was to evaluate the virological efficacy of new oral DAA's in HCV patients with MC. Methods: Retrospective cohort study in an integrated health care system with 3.8 million members in Southern California. Regional hepatitis C registry was accessed to identify chronic HCV patients treated with new DAA's. ICD code for cryoglobulinemic vasculitis and CPT codes for cryoglobulin were applied followed by manual chart review to identify HCV patients with MC. Demographic information, HCV genotype, viral load, prior HCV treatment, liver cirrhosis, MC clinical manifestations and other laboratory data were obtained through chart review. The primary endpoint was sustained virological response (SVR) at week 4. Results: 18 HCV-MC patients treated with new oral DAA's were identified (Image 1). The mean age was 63 years, 11 (61%) females, and 11 (61%) white. 10 (55%) patients were cirrhotic and 11 (61%) HCV treatment naïve. 9 patients received sofosbuvir/ribavirin, 4 sofosbuvir/ribavirin/peg interferon, 4 ledipasvir/sofosbuvir and 1 sofosbuvir/ simeprevir. All patients achieved end of treatment response (ETR). 16 out of 18 (88.88%) attained sustained virological response (SVR) at week 4; of these 16 patients, 12 have achieved SVR12 and 8 have SVR24 till date. The longest known SVR duration till date is 50 weeks. 80% of cirrhotics had SVR4. Conclusion: New DAA's are superior to past regimens in achieving SVR in this difficult to treat population.Figure 1

Is screening baby boomers for HCV enough? A call to screen for hepatitis C virus in persons from countries of high endemicity

Is screening baby boomers for <scp>HCV</scp> enough? A call to screen for hepatitis C virus in persons from countries of high endemicity

Beyond sofosbuvir: What opportunity exists for a better nucleoside/nucleotide to treat hepatitis C?

Sofosbuvir is a liver-targeting uridine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase recently approved by the FDA and EU regulators for treatment of patients infected with genotype 1, 2, 3 and 4 virus. The request for regulatory approval of the fixed-dose combination containing sofosbuvir and the NS5A inhibitor ledipasvir is also under review. Preclinical and clinical studies have shown that sofosbuvir is effective, safe and well tolerated. Review of sofosbuvir’s preclinical and clinical profile reveals a drug that has the potential to become the backbone of standard of care. Pursuit of a next generation nucleos(t)ide HCV inhibitor that could compete with sofosbuvir would need to address whatever limitations sofosbuvir exhibits. These include reduced efficacy in genotype 3 patients and use in severe renally impaired patients or those patients currently on drugs that are inducers of P-glycoprotein. However, it has been shown that reduced efficacy in genotype 3 is largely eliminated when sofosbuvir is combined with another oral DAA. Next-generation inhibitors would also benefit by enabling a reduced duration of therapy and an orthogonal resistance profile. The more recent group of nucleos(t)ides in clinical development maintains similarities to sofosbuvir, in that they are uridine nucleotide prodrugs. The question therefore remains whether these new agents will be sufficiently differentiated from sofosbuvir to provide any additional benefit to patients. This paper forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”

Su1059 Treatment Satisfaction in Clinical Trial (Aviator) Patients Treated With Interferon-Free, Oral DAA Regimens: External Validation of the Hepatitis C Virus (HCV) Treatment Satisfaction (HCVTSAT) Instrument

Background: The HCV-PRO is a validated disease-specific patient reported outcome (PRO) instrument. This analysis reports on HCV-infected patient response in a trial of oral DAA therapy and assesses psychometric properties of the French-translated HCV-PRO. Method: French Genotype 1 patients in the multinational AVIATOR trial of interferon-free DAA therapy responded to theHCV-PRO, SF-36v.2, and EQ-5D 5L+VAS. HCV-PROwas translated under Harmonization standards. Approved French-language SF-36 and EQ-5Dwere included for psychometric comparison. Analyses of response were performed at Baseline, week 8 (Wk8), End of Treatment (EOT), and 24 week follow-up (PTW24), and included change from baseline. Internal consistency/reliability of HCV-PRO items and total score were evaluated using Cronbach's alpha. Convergent validity was assessed through Pearson's correlation (0.5-0.9=moderate-strong) to SF-36 MCS/PCS and EQ-5D VAS. Discriminant validity was assessed by dichotomizing HCV-PRO score on EQ-5D Anxiety/Depression and Pain/Discomfort dimensions (none versus some). Results: Demographics (N=58): 48% female, 88% white, 45% ≥50 years of age, 45% Genotype 1a, 86% IL28B non-CC. Clinical response (SVR24) was 93.1%. All PRO scores were minimally changed during treatment (Wk8, EOT). Mean HCV-PRO score at PTW24 was improved (p<0.03) over baseline. Cronbach's alpha for HCV-PRO items and total scores were 0.44-0.95. HCV-PRO total score exhibited moderateto-high correlation with SF-36 MCS/PCS and EQ-5D VAS total scores (r=0.54-0.87). HCVPRO scores were lower in patients with anxiety/depression or pain/discomfort (p<0.01). Conclusion: The French-translated HCV-PRO is a valid, responsive, disease-specific instrument. HCV-PRO score changed minimally during oral DAA treatment and improved over baseline after therapy.