Sonal Kumar

Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial

Context Options are needed when initial therapy fails for hepatitis C virus (HCV) infection. Contribution In a phase 2 trial, treatment-experienced patients with genotype 3 HCV infection who either did not have cirrhosis or had compensated cirrhosis, as well as patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor plus peginterferon or ribavirin, received sofosbuvir plus 1 of 2 doses of velpatasvir with or without ribavirin. Sustained virologic response rates 12 weeks after treatment were high in all groups that received sofosbuvir plus 100 mg of velpatasvir. Treatment was well-tolerated. Caution The number of patients was small. Implication Larger trials of sofosbuvir plus velpatasvir are indicated for patients with HCV infection for whom initial therapy fails. Of the 6 hepatitis C virus (HCV) genotypes, 1 and 3 are the most common and account for approximately 46% and 22% of all global infections, respectively (1). Chronic infection with genotype 1 HCV is most prevalent in the Americas, Europe, and China, and genotype 3 HCV infection is most prevalent in India, Pakistan, and Southeast Asia (1). With the advent of direct-acting antiviral agents, effective interferon-free combination regimens are now available for most patients chronically infected with genotype 1 or 3 HCV (2, 3). However, some subgroups of patients do not achieve optimal rates of sustained virologic response (SVR) with existing 12-week regimensin particular, cirrhotic patients with genotype 1 or 3 HCV infection who previously received unsuccessful treatment of HCV infection (46). These patients, who are at increased risk for progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications, have a medical need for more effective and well-tolerated treatment (7, 8). Velpatasvir (Gilead Sciences) is a novel inhibitor of the HCV NS5A protein, which is involved in HCV replication, virion assembly, and modulation of host cellular response. Velpatasvir (formerly GS-5816) has demonstrated potent pangenotypic antiviral activity in vitro (9) and in a 3-day monotherapy study in patients with genotype 1, 2, 3, or 4 HCV infection (10, 11). Pharmacology studies showed no clinically important drug interactions between sofosbuvir and velpatasvir (12). A recent phase 2 study demonstrated the safety and efficacy of 12 weeks of the combination of sofosbuvir and velpatasvir in treatment-naive patients with genotype 1 to 6 HCV infection, with rates of SVR at week 12 after treatment (SVR12) of 93% to 100% (13). We evaluated the antiviral activity, safety, and tolerability of sofosbuvir administered with 25 or 100 mg of velpatasvir with and without ribavirin for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection. Because previously treated patients have historically had a poorer response than treatment-naive patients, we chose to evaluate sofosbuvir plus velpatasvir with ribavirin, as well as sofosbuvir plus velpatasvir alone. Methods Design Overview This phase 2, multicenter, randomized, open-label study was conducted from June 2013 (when the first patient was enrolled) to August 2014 (when the last patient completed follow-up). The study was originally designed to enroll 2 cohorts of patients with chronic genotype 3 HCV infection who had not achieved SVR after previous therapy with an interferon-based regimenapproximately 100 patients without cirrhosis and 100 patients with compensated cirrhosis. Favorable results in treatment-naive patients with genotype 1 HCV infection in a phase 2 trial of similar design (13) prompted us to amend our protocol to enroll a third cohort of approximately 100 patients with chronic genotype 1 HCV infection who did not achieve SVR after previous therapy with an approved or experimental NS3/4A protease inhibitor in combination with peginterferon and ribavirin. Up to 50% of patients with genotype 1 HCV infection could have compensated cirrhosis. The protocol was approved by the institutional ethics committees at all sites, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Setting and Participants The study was conducted at 58 clinical sites: 7 in Australia, 2 in New Zealand, and 49 in the United States. Some patients were recruited partly through a posting of study details on ClinicalTrials.gov and others through referral by their treating physicians. Adults (aged 18 years) with HCV RNA levels greater than 10000 IU/mL were eligible. The HCV RNA genotype was determined by the central laboratory using the Versant HCV Genotype 2.0 Assay (LiPA) (Siemens). If results were inconclusive, we used the TruGene HCV 5NC Genotyping Kit (Siemens) with the OpenGene DNA Sequencing System (Siemens). The presence of cirrhosis was established by liver biopsy, a FibroTest score greater than 0.75 and an aspartate aminotransferaseplatelet ratio index greater than 2 during screening, or a FibroScan value greater than 12.5 kPa. Exclusion criteria were hepatic decompensation or co-infection with hepatitis B virus or HIV; aminotransferase level more than 10 times the upper limit of normal; direct bilirubin level more than 1.5 times the upper limit of normal; platelet count less than 90109 cells/L; hemoglobin A1c level greater than 8.5%; creatinine clearance rate less than 60 mL/min/1.73 m2, as calculated by the CockcroftGault equation; hemoglobin level less than 11 g/dL for female patients or less than 12 g/dL for male patients; albumin level less than 454.55 mol/L; and prothrombin time (international normalized ratio) greater than 1.5 times the upper limit of normal. To be eligible, patients must not have achieved SVR after previous treatment of HCV infection and must not have discontinued the previous regimen due to an adverse event. Patients with genotype 3 HCV infection with previous exposure to an approved or experimental HCV-specific direct-acting antiviral agent were excluded. Full eligibility criteria are listed in the study protocol (Supplement). All patients provided written informed consent before screening. Supplement. Study Protocol Randomization and Interventions Three cohorts of eligible patients were enrolled: treatment-experienced patients with genotype 3 HCV infection without cirrhosis, treatment-experienced patients with genotype 3 HCV infection with compensated cirrhosis, and patients with genotype 1 HCV infection whose previous treatment with a protease inhibitor and interferon-based regimen was unsuccessful. Within each cohort, patients were randomly assigned to 4 groups (by a 1:1:1:1 ratio), each of which received 12 weeks of a single oral daily dose of 400 mg of sofosbuvir plus 25 mg of velpatasvir, 25 mg of velpatasvir with ribavirin, 100 mg of velpatasvir, or 100 mg of velpatasvir with ribavirin (Figure). Velpatasvir was orally administered in single daily doses of either 25 or 100 mg. Ribavirin was administered orally in a divided daily dose determined by body weight: 1000 mg daily in patients weighing less than 75 kg and 1200 mg daily in patients weighing 75 kg or greater. Figure. Study flow diagram. Patients in groups 9 to 12 were enrolled after patients in groups 1 to 8 had completed the trial and were assessed for efficacy. HCV = hepatitis C virus; RBV = ribavirin; SOF = sofosbuvir; VEL = velpatasvir. Random assignment of patients was managed with an interactive Web-response system (Bracket). A statistician employed by the sponsor (L.H.) generated the randomization code using SAS, version 9.2 (SAS Institute), which was validated by another statistician employed by the sponsor. The randomization was stratified by cohort. Within cohort 3 (patients with genotype 1 HCV infection), randomization was stratified by genotype 1 subtype (1a or 1b) and cirrhosis status (presence or absence). Investigators (Appendix), patients, and trial personnel were not blinded to treatment assignment. Outcomes and Follow-up The primary efficacy outcome measure was SVR12, defined as a serum HCV RNA level below the lower limit of quantification (LLOQ) 12 weeks after completion of treatment. We measured HCV RNA levels with the Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Diagnostics), in combination with the High Pure System Viral Nucleic Acid Kit (Roche Diagnostics), and used an LLOQ of 25 IU/mL. Secondary efficacy outcome measures included the proportion of patients with virologic failure, which was defined as either on-treatment virologic failure (HCV RNA level at or above the LLOQ after 8 weeks of therapy, confirmed >1 log10 increase in HCV RNA level from nadir, or confirmed HCV RNA level at or above the LLOQ after 2 consecutive HCV RNA levels less than the LLOQ) or relapse (HCV RNA level at or above the LLOQ during the posttreatment period or HCV RNA levels less than the LLOQ at the end of treatment). Other secondary efficacy outcome measures (SVR4, SVR24, and HCV RNA levels less than the LLOQ by study visit and HCV RNA levels and change from baseline in HCV RNA levels through week 12) are not reported here. The primary safety outcome measure was any adverse event leading to permanent withdrawal of study drugs. Safety assessments during treatment and up to 30 days after treatment included reports of adverse events, standard laboratory testing, 12-lead electrocardiography, assessment of vital signs, and symptom-driven physical examinations. Adverse events were coded using the Medical Dictionary for Regulatory Activities and graded by severity by the investigator according to the Gilead Sciences Grading Scale for Severity of Adverse Events and Laboratory Abnormalities. Deep sequencing of the HCV NS5A and NS5B gene was done from pretreatment plasma samples from all enrolled patients and from posttreatment samples from all patients with virologic failure. The HCV NS5A and NS5B coding regions were amplified by DDL Diagnostic Laboratory (Rijswijk, The Netherlands) with standard reverse transcr

Antiviral therapy with nucleotide polymerase inhibitors for chronic hepatitis C

The treatment of hepatitis C virus (HCV) has made significant advances with the development of new direct-acting antivirals. Nucleotide polymerase inhibitors are one class of these new medications that have been shown to be highly effective, safe and well tolerated as part of an antiviral regimen. Sofosbuvir has become the first drug in this class to be approved for clinical use, supported by results from extensive phase II and phase III clinical trials. This review will further discuss nucleotide polymerase inhibitors, including the data supporting their use as part of interferon-free HCV treatment regimens.

Association between Liver Disease and Intracranial Hemorrhage.

BACKGROUND Liver disease is common and associated with clinical and laboratory evidence of coagulopathy. The association between liver disease and intracranial hemorrhage (ICH) remains unclear. Our aim was to assess whether liver disease increases the risk of ICH. METHODS We performed a retrospective cohort study based on administrative claims data from California, Florida, and New York acute care hospitals from 2005 through 2011. Of a random 5% sample, we included patients discharged from the emergency department or hospital after a diagnosis of liver disease and compared them to patients without liver disease. Patients with cirrhotic liver disease were additionally analyzed separately. Kaplan-Meier survival statistics were used to calculate cumulative rates of incident ICH, and Cox proportional hazard analysis was used to adjust for demographic characteristics, vascular disease, and Elixhauser comorbidities. Multiple models tested the robustness of our results. RESULTS Among 1,909,816 patients with a mean follow-up period of 4.1 (±1.8) years, the cumulative rate of ICH after a diagnosis of liver disease was 1.70% (95% confidence interval [CI], 1.55%-1.87%) compared to .40% (95% CI, .39%-.41%) in patients without liver disease (P <.001 by the log-rank test). Liver disease remained associated with an increased hazard of ICH after adjustment for demographic characteristics and vascular risk factors (hazard ratio [HR], 1.8; 95% CI, 1.6-2.0). This was attenuated in models additionally adjusted for general comorbidities (HR, 1.3; 95% CI, 1.2-1.5). CONCLUSIONS There is a modest, independent association between liver disease and the risk of ICH.

Clinical Presentation and Outcomes of Autoimmune Hepatitis in Inflammatory Bowel Disease.

Nearly one-third of patients with inflammatory bowel disease (IBD) have abnormal liver tests, which can be indicative of underlying hepatic disease. Primary sclerosing cholangitis has a clear association with ulcerative colitis, but other autoimmune disorders such as autoimmune hepatitis (AIH) have also been associated with IBD. AIH may also occur in the setting of an overlap syndrome or in the setting of medications, particularly tumor necrosis factor alpha inhibitors. Importantly, some studies have shown that IBD patients with AIH fail treatment more frequently than IBD patients without AIH. This review will focus on the clinical characteristics, diagnosis, and management of autoimmune hepatitis in inflammatory bowel disease patients.

Sofosbuvir plus velpatasvir combination therapy for treatment- Experienced patients with genotype 1 or 3 Hepatitis c virus infection

Context Options are needed when initial therapy fails for hepatitis C virus (HCV) infection. Contribution In a phase 2 trial, treatment-experienced patients with genotype 3 HCV infection who either did not have cirrhosis or had compensated cirrhosis, as well as patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor plus peginterferon or ribavirin, received sofosbuvir plus 1 of 2 doses of velpatasvir with or without ribavirin. Sustained virologic response rates 12 weeks after treatment were high in all groups that received sofosbuvir plus 100 mg of velpatasvir. Treatment was well-tolerated. Caution The number of patients was small. Implication Larger trials of sofosbuvir plus velpatasvir are indicated for patients with HCV infection for whom initial therapy fails. Of the 6 hepatitis C virus (HCV) genotypes, 1 and 3 are the most common and account for approximately 46% and 22% of all global infections, respectively (1). Chronic infection with genotype 1 HCV is most prevalent in the Americas, Europe, and China, and genotype 3 HCV infection is most prevalent in India, Pakistan, and Southeast Asia (1). With the advent of direct-acting antiviral agents, effective interferon-free combination regimens are now available for most patients chronically infected with genotype 1 or 3 HCV (2, 3). However, some subgroups of patients do not achieve optimal rates of sustained virologic response (SVR) with existing 12-week regimensin particular, cirrhotic patients with genotype 1 or 3 HCV infection who previously received unsuccessful treatment of HCV infection (46). These patients, who are at increased risk for progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications, have a medical need for more effective and well-tolerated treatment (7, 8). Velpatasvir (Gilead Sciences) is a novel inhibitor of the HCV NS5A protein, which is involved in HCV replication, virion assembly, and modulation of host cellular response. Velpatasvir (formerly GS-5816) has demonstrated potent pangenotypic antiviral activity in vitro (9) and in a 3-day monotherapy study in patients with genotype 1, 2, 3, or 4 HCV infection (10, 11). Pharmacology studies showed no clinically important drug interactions between sofosbuvir and velpatasvir (12). A recent phase 2 study demonstrated the safety and efficacy of 12 weeks of the combination of sofosbuvir and velpatasvir in treatment-naive patients with genotype 1 to 6 HCV infection, with rates of SVR at week 12 after treatment (SVR12) of 93% to 100% (13). We evaluated the antiviral activity, safety, and tolerability of sofosbuvir administered with 25 or 100 mg of velpatasvir with and without ribavirin for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection. Because previously treated patients have historically had a poorer response than treatment-naive patients, we chose to evaluate sofosbuvir plus velpatasvir with ribavirin, as well as sofosbuvir plus velpatasvir alone. Methods Design Overview This phase 2, multicenter, randomized, open-label study was conducted from June 2013 (when the first patient was enrolled) to August 2014 (when the last patient completed follow-up). The study was originally designed to enroll 2 cohorts of patients with chronic genotype 3 HCV infection who had not achieved SVR after previous therapy with an interferon-based regimenapproximately 100 patients without cirrhosis and 100 patients with compensated cirrhosis. Favorable results in treatment-naive patients with genotype 1 HCV infection in a phase 2 trial of similar design (13) prompted us to amend our protocol to enroll a third cohort of approximately 100 patients with chronic genotype 1 HCV infection who did not achieve SVR after previous therapy with an approved or experimental NS3/4A protease inhibitor in combination with peginterferon and ribavirin. Up to 50% of patients with genotype 1 HCV infection could have compensated cirrhosis. The protocol was approved by the institutional ethics committees at all sites, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Setting and Participants The study was conducted at 58 clinical sites: 7 in Australia, 2 in New Zealand, and 49 in the United States. Some patients were recruited partly through a posting of study details on ClinicalTrials.gov and others through referral by their treating physicians. Adults (aged 18 years) with HCV RNA levels greater than 10000 IU/mL were eligible. The HCV RNA genotype was determined by the central laboratory using the Versant HCV Genotype 2.0 Assay (LiPA) (Siemens). If results were inconclusive, we used the TruGene HCV 5NC Genotyping Kit (Siemens) with the OpenGene DNA Sequencing System (Siemens). The presence of cirrhosis was established by liver biopsy, a FibroTest score greater than 0.75 and an aspartate aminotransferaseplatelet ratio index greater than 2 during screening, or a FibroScan value greater than 12.5 kPa. Exclusion criteria were hepatic decompensation or co-infection with hepatitis B virus or HIV; aminotransferase level more than 10 times the upper limit of normal; direct bilirubin level more than 1.5 times the upper limit of normal; platelet count less than 90109 cells/L; hemoglobin A1c level greater than 8.5%; creatinine clearance rate less than 60 mL/min/1.73 m2, as calculated by the CockcroftGault equation; hemoglobin level less than 11 g/dL for female patients or less than 12 g/dL for male patients; albumin level less than 454.55 mol/L; and prothrombin time (international normalized ratio) greater than 1.5 times the upper limit of normal. To be eligible, patients must not have achieved SVR after previous treatment of HCV infection and must not have discontinued the previous regimen due to an adverse event. Patients with genotype 3 HCV infection with previous exposure to an approved or experimental HCV-specific direct-acting antiviral agent were excluded. Full eligibility criteria are listed in the study protocol (Supplement). All patients provided written informed consent before screening. Supplement. Study Protocol Randomization and Interventions Three cohorts of eligible patients were enrolled: treatment-experienced patients with genotype 3 HCV infection without cirrhosis, treatment-experienced patients with genotype 3 HCV infection with compensated cirrhosis, and patients with genotype 1 HCV infection whose previous treatment with a protease inhibitor and interferon-based regimen was unsuccessful. Within each cohort, patients were randomly assigned to 4 groups (by a 1:1:1:1 ratio), each of which received 12 weeks of a single oral daily dose of 400 mg of sofosbuvir plus 25 mg of velpatasvir, 25 mg of velpatasvir with ribavirin, 100 mg of velpatasvir, or 100 mg of velpatasvir with ribavirin (Figure). Velpatasvir was orally administered in single daily doses of either 25 or 100 mg. Ribavirin was administered orally in a divided daily dose determined by body weight: 1000 mg daily in patients weighing less than 75 kg and 1200 mg daily in patients weighing 75 kg or greater. Figure. Study flow diagram. Patients in groups 9 to 12 were enrolled after patients in groups 1 to 8 had completed the trial and were assessed for efficacy. HCV = hepatitis C virus; RBV = ribavirin; SOF = sofosbuvir; VEL = velpatasvir. Random assignment of patients was managed with an interactive Web-response system (Bracket). A statistician employed by the sponsor (L.H.) generated the randomization code using SAS, version 9.2 (SAS Institute), which was validated by another statistician employed by the sponsor. The randomization was stratified by cohort. Within cohort 3 (patients with genotype 1 HCV infection), randomization was stratified by genotype 1 subtype (1a or 1b) and cirrhosis status (presence or absence). Investigators (Appendix), patients, and trial personnel were not blinded to treatment assignment. Outcomes and Follow-up The primary efficacy outcome measure was SVR12, defined as a serum HCV RNA level below the lower limit of quantification (LLOQ) 12 weeks after completion of treatment. We measured HCV RNA levels with the Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Diagnostics), in combination with the High Pure System Viral Nucleic Acid Kit (Roche Diagnostics), and used an LLOQ of 25 IU/mL. Secondary efficacy outcome measures included the proportion of patients with virologic failure, which was defined as either on-treatment virologic failure (HCV RNA level at or above the LLOQ after 8 weeks of therapy, confirmed >1 log10 increase in HCV RNA level from nadir, or confirmed HCV RNA level at or above the LLOQ after 2 consecutive HCV RNA levels less than the LLOQ) or relapse (HCV RNA level at or above the LLOQ during the posttreatment period or HCV RNA levels less than the LLOQ at the end of treatment). Other secondary efficacy outcome measures (SVR4, SVR24, and HCV RNA levels less than the LLOQ by study visit and HCV RNA levels and change from baseline in HCV RNA levels through week 12) are not reported here. The primary safety outcome measure was any adverse event leading to permanent withdrawal of study drugs. Safety assessments during treatment and up to 30 days after treatment included reports of adverse events, standard laboratory testing, 12-lead electrocardiography, assessment of vital signs, and symptom-driven physical examinations. Adverse events were coded using the Medical Dictionary for Regulatory Activities and graded by severity by the investigator according to the Gilead Sciences Grading Scale for Severity of Adverse Events and Laboratory Abnormalities. Deep sequencing of the HCV NS5A and NS5B gene was done from pretreatment plasma samples from all enrolled patients and from posttreatment samples from all patients with virologic failure. The HCV NS5A and NS5B coding regions were amplified by DDL Diagnostic Laboratory (Rijswijk, The Netherlands) with standard reverse transcr

PORTAL VEIN THROMBOSIS PREVALENCE AND ASSOCIATED MORTALITY IN CIRRHOSIS IN A NATIONALLY REPRESENTATIVE INPATIENT COHORT: PORTAL VEIN THROMBOSIS PREVALENCE AND ASSOCIATED MORTALITY IN CIRRHOSIS IN A NATIONALLY REPRESENTATIVE INPATIENT COHORT

Portal vein thrombosis (PVT) is increasingly common in cirrhotics, but its impact on mortality and outcomes is unclear. Studies evaluating PVT have been limited by small sample size. This study analyzes the trend of the prevalence of PVT and its associated mortality in hospitalized decompensated cirrhotics.

Social media: Why AASLD and its members must lead the conversation

In the first issue of HEPATOLOGY, founding editor Irwin Arias wrote of his hope that the journal would serve as a scientific home for those of us who focus on the liver, and enlighten us regarding exciting new paths in our field. While he was referring to advances in biology, social media presents an exciting new opportunity unfolding before our eyes. In the spirit of Dr. Arias’ vision, it is fitting to comment on why the American Association for the Study of Liver Diseases (AASLD) should lead and shape the conversation about liver health on these platforms. Social media has taken the world by storm. In just over 10 years, the percentage of U.S. adults using at least one social media platform has skyrocketed from 5% in 2005 to 69% in 2018 (Fig. 1). Among those aged 18-29, adoption now reaches 88%. There have even been social networks developed specifically for health care providers. One of these claims to reach 70% of all U.S. doctors and 90% of fourth-year medical students. The speed and scale of this paradigm shift are staggering: Telephones took more than 60 years to approach the level of adoption that social media has achieved in just 10. The AASLD’s mission is “to advance and disseminate the science and practice of hepatology, and to promote liver health and quality patient care.” Today, the number of conversations held, articles shared, and information sought and discovered across social networks is almost beyond calculation. Search Twitter for “liver health” and find information on new therapies, material on homeopathic remedies, and the latest articles related to our field. Search Facebook for “hepatitis” and find a list of groups in which patients discuss their experiences. Search YouTube for “liver disease” and find videos promising to explain the disorder, expose warning signs of toxins, or teach viewers how to repair liver damage. The only way to ensure that trusted, science-based information is at the forefront of liver discussions on social media is by leading and contributing to them. Whatever your role in the science and practice of liver health, we entreat you to join the conversation and take advantage of this powerful tool in advancing our mission. Researchers can share their work and collaborate with others. Clinicians can engage with peers on difficult cases, learn about new treatments, and build their reputations as trusted experts. All can provide useful, reliable content for patients and caregivers, educating them and hedging against misinformation. The Crohn’s & Colitis Congress was held as we were writing this commentary. Social media conversation during the event ranged from the latest controversies in inflammatory bowel disease to top-notch poster presentations from experts. By following the @AmerGastroAssn Twitter handle (https://twitter. com/AmerGastroAssn), or perusing the #CCCongress hashtag (https://twitter.com/hashtag/CCCongress), someone could gain ideas for patients, find contacts, and even get an abbreviated briefing on the current status of the field. With social media, they could do this in real time from virtually anywhere in the world. The medical community is studying the impact of social media use by patients, and findings are promising. In December 2016, the Journal of the American College of Radiology published a report on how social media is changing the patient experience. The authors conclude that it is redefining how patients communicate with each other and find information from experts, and offer suggestions for using social media to improve the patient experience. They describe how social media can help improve the information patients find online about physicians, explore how it may improve interactions with online patient communities, and discuss how it can be used to curate, interpret, and organize scientific information for patients seeking peer-reviewed literature and topic-specific information. Abbreviation: AASLD, American Association for the Study of Liver Diseases.

Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus InfectionA Randomized TrialSofosbuvir Plus Velpatasvir for Patients With HCV Infection

Context Options are needed when initial therapy fails for hepatitis C virus (HCV) infection. Contribution In a phase 2 trial, treatment-experienced patients with genotype 3 HCV infection who either did not have cirrhosis or had compensated cirrhosis, as well as patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor plus peginterferon or ribavirin, received sofosbuvir plus 1 of 2 doses of velpatasvir with or without ribavirin. Sustained virologic response rates 12 weeks after treatment were high in all groups that received sofosbuvir plus 100 mg of velpatasvir. Treatment was well-tolerated. Caution The number of patients was small. Implication Larger trials of sofosbuvir plus velpatasvir are indicated for patients with HCV infection for whom initial therapy fails. Of the 6 hepatitis C virus (HCV) genotypes, 1 and 3 are the most common and account for approximately 46% and 22% of all global infections, respectively (1). Chronic infection with genotype 1 HCV is most prevalent in the Americas, Europe, and China, and genotype 3 HCV infection is most prevalent in India, Pakistan, and Southeast Asia (1). With the advent of direct-acting antiviral agents, effective interferon-free combination regimens are now available for most patients chronically infected with genotype 1 or 3 HCV (2, 3). However, some subgroups of patients do not achieve optimal rates of sustained virologic response (SVR) with existing 12-week regimensin particular, cirrhotic patients with genotype 1 or 3 HCV infection who previously received unsuccessful treatment of HCV infection (46). These patients, who are at increased risk for progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications, have a medical need for more effective and well-tolerated treatment (7, 8). Velpatasvir (Gilead Sciences) is a novel inhibitor of the HCV NS5A protein, which is involved in HCV replication, virion assembly, and modulation of host cellular response. Velpatasvir (formerly GS-5816) has demonstrated potent pangenotypic antiviral activity in vitro (9) and in a 3-day monotherapy study in patients with genotype 1, 2, 3, or 4 HCV infection (10, 11). Pharmacology studies showed no clinically important drug interactions between sofosbuvir and velpatasvir (12). A recent phase 2 study demonstrated the safety and efficacy of 12 weeks of the combination of sofosbuvir and velpatasvir in treatment-naive patients with genotype 1 to 6 HCV infection, with rates of SVR at week 12 after treatment (SVR12) of 93% to 100% (13). We evaluated the antiviral activity, safety, and tolerability of sofosbuvir administered with 25 or 100 mg of velpatasvir with and without ribavirin for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection. Because previously treated patients have historically had a poorer response than treatment-naive patients, we chose to evaluate sofosbuvir plus velpatasvir with ribavirin, as well as sofosbuvir plus velpatasvir alone. Methods Design Overview This phase 2, multicenter, randomized, open-label study was conducted from June 2013 (when the first patient was enrolled) to August 2014 (when the last patient completed follow-up). The study was originally designed to enroll 2 cohorts of patients with chronic genotype 3 HCV infection who had not achieved SVR after previous therapy with an interferon-based regimenapproximately 100 patients without cirrhosis and 100 patients with compensated cirrhosis. Favorable results in treatment-naive patients with genotype 1 HCV infection in a phase 2 trial of similar design (13) prompted us to amend our protocol to enroll a third cohort of approximately 100 patients with chronic genotype 1 HCV infection who did not achieve SVR after previous therapy with an approved or experimental NS3/4A protease inhibitor in combination with peginterferon and ribavirin. Up to 50% of patients with genotype 1 HCV infection could have compensated cirrhosis. The protocol was approved by the institutional ethics committees at all sites, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Setting and Participants The study was conducted at 58 clinical sites: 7 in Australia, 2 in New Zealand, and 49 in the United States. Some patients were recruited partly through a posting of study details on ClinicalTrials.gov and others through referral by their treating physicians. Adults (aged 18 years) with HCV RNA levels greater than 10000 IU/mL were eligible. The HCV RNA genotype was determined by the central laboratory using the Versant HCV Genotype 2.0 Assay (LiPA) (Siemens). If results were inconclusive, we used the TruGene HCV 5NC Genotyping Kit (Siemens) with the OpenGene DNA Sequencing System (Siemens). The presence of cirrhosis was established by liver biopsy, a FibroTest score greater than 0.75 and an aspartate aminotransferaseplatelet ratio index greater than 2 during screening, or a FibroScan value greater than 12.5 kPa. Exclusion criteria were hepatic decompensation or co-infection with hepatitis B virus or HIV; aminotransferase level more than 10 times the upper limit of normal; direct bilirubin level more than 1.5 times the upper limit of normal; platelet count less than 90109 cells/L; hemoglobin A1c level greater than 8.5%; creatinine clearance rate less than 60 mL/min/1.73 m2, as calculated by the CockcroftGault equation; hemoglobin level less than 11 g/dL for female patients or less than 12 g/dL for male patients; albumin level less than 454.55 mol/L; and prothrombin time (international normalized ratio) greater than 1.5 times the upper limit of normal. To be eligible, patients must not have achieved SVR after previous treatment of HCV infection and must not have discontinued the previous regimen due to an adverse event. Patients with genotype 3 HCV infection with previous exposure to an approved or experimental HCV-specific direct-acting antiviral agent were excluded. Full eligibility criteria are listed in the study protocol (Supplement). All patients provided written informed consent before screening. Supplement. Study Protocol Randomization and Interventions Three cohorts of eligible patients were enrolled: treatment-experienced patients with genotype 3 HCV infection without cirrhosis, treatment-experienced patients with genotype 3 HCV infection with compensated cirrhosis, and patients with genotype 1 HCV infection whose previous treatment with a protease inhibitor and interferon-based regimen was unsuccessful. Within each cohort, patients were randomly assigned to 4 groups (by a 1:1:1:1 ratio), each of which received 12 weeks of a single oral daily dose of 400 mg of sofosbuvir plus 25 mg of velpatasvir, 25 mg of velpatasvir with ribavirin, 100 mg of velpatasvir, or 100 mg of velpatasvir with ribavirin (Figure). Velpatasvir was orally administered in single daily doses of either 25 or 100 mg. Ribavirin was administered orally in a divided daily dose determined by body weight: 1000 mg daily in patients weighing less than 75 kg and 1200 mg daily in patients weighing 75 kg or greater. Figure. Study flow diagram. Patients in groups 9 to 12 were enrolled after patients in groups 1 to 8 had completed the trial and were assessed for efficacy. HCV = hepatitis C virus; RBV = ribavirin; SOF = sofosbuvir; VEL = velpatasvir. Random assignment of patients was managed with an interactive Web-response system (Bracket). A statistician employed by the sponsor (L.H.) generated the randomization code using SAS, version 9.2 (SAS Institute), which was validated by another statistician employed by the sponsor. The randomization was stratified by cohort. Within cohort 3 (patients with genotype 1 HCV infection), randomization was stratified by genotype 1 subtype (1a or 1b) and cirrhosis status (presence or absence). Investigators (Appendix), patients, and trial personnel were not blinded to treatment assignment. Outcomes and Follow-up The primary efficacy outcome measure was SVR12, defined as a serum HCV RNA level below the lower limit of quantification (LLOQ) 12 weeks after completion of treatment. We measured HCV RNA levels with the Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Diagnostics), in combination with the High Pure System Viral Nucleic Acid Kit (Roche Diagnostics), and used an LLOQ of 25 IU/mL. Secondary efficacy outcome measures included the proportion of patients with virologic failure, which was defined as either on-treatment virologic failure (HCV RNA level at or above the LLOQ after 8 weeks of therapy, confirmed >1 log10 increase in HCV RNA level from nadir, or confirmed HCV RNA level at or above the LLOQ after 2 consecutive HCV RNA levels less than the LLOQ) or relapse (HCV RNA level at or above the LLOQ during the posttreatment period or HCV RNA levels less than the LLOQ at the end of treatment). Other secondary efficacy outcome measures (SVR4, SVR24, and HCV RNA levels less than the LLOQ by study visit and HCV RNA levels and change from baseline in HCV RNA levels through week 12) are not reported here. The primary safety outcome measure was any adverse event leading to permanent withdrawal of study drugs. Safety assessments during treatment and up to 30 days after treatment included reports of adverse events, standard laboratory testing, 12-lead electrocardiography, assessment of vital signs, and symptom-driven physical examinations. Adverse events were coded using the Medical Dictionary for Regulatory Activities and graded by severity by the investigator according to the Gilead Sciences Grading Scale for Severity of Adverse Events and Laboratory Abnormalities. Deep sequencing of the HCV NS5A and NS5B gene was done from pretreatment plasma samples from all enrolled patients and from posttreatment samples from all patients with virologic failure. The HCV NS5A and NS5B coding regions were amplified by DDL Diagnostic Laboratory (Rijswijk, The Netherlands) with standard reverse transcr

Optimal Management of the Hepatitis C Patient: Review of the AASLD/IDSA Guidelines

Over the last few years, the treatment of hepatitis C has evolved dramatically with the introduction of direct-acting antivirals to the regimen. Now with the anticipated approval of multiple all-oral regimens, the use of interferon is likely to disappear in many countries. Already approved are simeprevir and sofosbuvir, and in the coming months, several additional drugs and regimens are expected to become part of clinical practice. The American Association for the Study of Liver Diseases and the Infectious Disease Society of America are assisting health care professionals by providing a nonpharmaceutical sponsored web-based Guidance document for management issues ranging from testing to treatment of hepatitis C-infected individuals. The Guidance is expected to be constantly updated as new information becomes available. This article will review the currently published treatment recommendations in the Guidance.

Mo1964 Alkaline Phosphatase Reduction Is Associated With Decreased Mortality and Risk of Colorectal Cancer or Dysplasia in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

G A A b st ra ct s statistics, the predictive accuracy of calprotectin in identifying patients with ineffective surveillance was 0.92 (area under the curve). A cutoff value of 545 μg/g indicated patients with ineffective surveillance with 86% sensitivity and 89% specificity, positive predictive value 52% and negative predictive value 98%). CONCLUSION: Fecal calprotectin testing prior to a scheduled surveillance colonoscopy can be used to identify IBD patients with active endoscopic inflammation in whom surveillance will probably be ineffective. Routine use of this test might prevent useless colonoscopies and can therefore be cost effective.