Rachel Silk

Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study.

Context The treatment of hepatitis C virus is changing rapidly with the introduction of interferon-free regimens that include direct-acting antiviral drugs, such as sofosbuvir. Although treatment generally results in sustained viral response, some patients have relapse after initial treatment. Contribution In a small, nonrandomized study, 14 patients who had relapse after treatment with sofosbuvir plus ribavirin were re-treated with sofosbuvir plus ledipasvir for 12 weeks. All patients, including those with advanced liver disease, achieved a sustained virologic response. The combination was generally well-tolerated. Implication Treatment with sofosbuvir plus ledipasvir may be efficacious in patients who have relapse after initial therapy for hepatitis C virus. Larger randomized studies of this promising combination are warranted. The Editors Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma and the leading indication for liver transplantation in Western countries (1, 2). Until recently, HCV treatment consisted of combination therapy with pegylated interferon (IFN) and ribavirin, with the addition of an HCV protease inhibitor (boceprevir or telaprevir) in recent years. In 2013, the U.S. Food and Drug Administration approved sofosbuvir plus ribavirin as the first IFN-free treatment of HCV genotype 2 or 3 and for patients with genotype 1 (GT-1) who are IFN-ineligible (37). Although sofosbuvir (an NS5B inhibitor) plus ribavirin is well-tolerated and effective with sustained virologic response (SVR) rates from 68% to 76% in patients with HCV GT-1 (8, 9), modest rates of relapse in patients with advanced liver disease and transplant recipients have been seen (8, 10, 11). Recent studies using sofosbuvir combined with ledipasvir (an NS5A inhibitor) for 12 weeks demonstrated high SVR rates (95% to 99%) in treatment-naive patients with HCV GT-1 (1215). Ledipasvir has potent antiviral activity against the S282T resistance-associated variant, known to reduce susceptibility to sofosbuvir in vitro (16). As previously reported, 17 of 54 patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study had relapse after treatment (8). We hypothesized that the combination of a second potent direct-acting antiviral agent (DAA) with sofosbuvir could result in SVR, even in patients with relapse after sofosbuvir plus ribavirin therapy and who may harbor the S282T mutation. To test this hypothesis, we re-treated those patients with sofosbuvir plus ledipasvir for 12 weeks. Methods Design Overview All patients who had relapse after 24 weeks of treatment with sofosbuvir plus ribavirin in the NIAID SPARE study (8) were offered re-treatment with sofosbuvir plus ledipasvir in the ongoing, phase 2a, open-label NIAID SYNERGY study (ClinicalTrials.gov: NCT01805882). Of the 17 eligible patients, 3 did not participate in the study. Fourteen patients enrolled and were treated with 400 mg of sofosbuvir and 90 mg of ledipasvir, administered daily as a single combination tablet, for 12 weeks. Setting and Patients The trial was conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and at community clinics that are part of the District of Columbia Partnership for HIV/AIDS Progress in Washington, DC. Written informed consent, which was approved by the NIAID Institutional Review Board, was obtained from all study patients. Eligibility criteria included documented HCV GT-1 infection and relapse in the NIAID SPARE study (8). Liver fibrosis stage was determined by biopsy within 3 years of enrollment in the NIAID SPARE study. The study was approved by the NIAID Institutional Review Board. It was conducted in adherence to the Good Clinical Practice guidelines and with regulatory requirements consistent with the Declaration of Helsinki. Outcomes and Follow-up Efficacy Assessments Plasma HCV RNA levels were measured using the Abbott RealTime HCV assay, with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL, or the Roche Cobas TaqMan HCV assay, version 2.0, with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL. Safety Assessments Patients were closely monitored for adverse events. Clinical laboratory results were assessed while receiving therapy (4, 8, and 12 weeks) and afterward (2, 4, 8, and 12 weeks after treatment). Adverse events were graded from 1 (mild) to 4 (severe), according to the NIAID Division of AIDS Toxicity Table (version 1.0). Interleukin-28B Genotyping Interleukin-28B genotype (rs12979860) was determined as previously described (8). Clinical End Points The primary end point was the proportion of patients with unquantifiable plasma HCV viral load 12 weeks after treatment completion. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes. Statistical Analysis Primary safety and efficacy data were analyzed by intention-to-treat (all patients who initiated study medication). Missing virologic data were imputed if data from preceding and succeeding time points were obtained. Baseline demographics were described using frequency statistics. Comparisons were calculated using either nonparametric tests or t tests with GraphPad Prism, version 6.0 (GraphPad Software). Role of the Funding Source This study was funded in part by the National Cancer Institute, the intramural programs of the NIH Clinical Center and NIAID, and a Collaborative Research and Development Agreement between the NIH and Gilead Sciences. The study sponsor was the Regulatory Compliance and Human Participants Protection Branch of the NIAID. The sponsor reviewed the study and provided oversight. However, it did not play a role in designing the study; collecting, analyzing, or interpreting the data; or the preparation, review, approval, or submission of the manuscript for publication. All study medications were provided by Gilead Sciences, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients Most study patients were black men with an unfavorable interleukin-28B non-CC genotype (Table 1). There was a high representation of patients with HCV GT-1a infection, increased baseline HCV viral load (>800000 IU/mL), increased body mass index (>30 kg/m2), and advanced liver disease (Knodell Histology Activity Index score of 3 or 4) (17). Table 1. Baseline Characteristics of Study Patients Presence of S282T Mutation At the time of relapse after sofosbuvir plus ribavirin treatment in the SPARE trial, 13 of 14 patients had wild-type virus by population sequencing (Supplement). The 1 exception achieved unquantifiable HCV RNA levels by week 2 of therapy in SPARE and the virus remained undetectable through the end of treatment. He missed his visit at 26 weeks (2 weeks after treatment), but at 28 weeks (4 weeks after treatment), his HCV viral load was 374 IU/mL and the S282T mutation was readily detected by population sequencing. By 36 weeks (12 weeks after treatment), his HCV viral load was 81286 IU/mL and the S282T mutation was no longer detectable. He initiated sofosbuvir plus ledipasvir treatment 50 weeks after relapse. Supplement. HCV Resistance Mutations Virologic Response Each of the 14 patients treated with sofosbuvir plus ledipasvir had HCV RNA levels below the lower limit of quantification by 4 weeks (Roche Cobas TaqMan HCV Assay, version 2.0), which was maintained through the end of treatment (12 weeks). All patients achieved SVR 12 weeks after completion of treatment. Changes in Hemoglobin Levels No significant change in hemoglobin levels during sofosbuvir plus ledipasvir treatment was seen, in contrast to the decrease seen with sofosbuvir plus ribavirin. The mean hemoglobin level change was 0.07 g/L versus 11.70 g/L at 4 weeks (P=0.01), 0.5 g/L versus 12.6 g/L at 8 weeks (P=0.01), and 3.1 g/L versus 12.1 g/L at 12 weeks (P=0.06) with sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin, respectively. No participant had a decrease in hemoglobin level of 15.0 g/L or greater with sofosbuvir plus ledipasvir compared with 8 of 14 (57%) with sofosbuvir plus ribavirin. Changes in Renal Function Renal variables did not change significantly over the course of treatment, although a single participant with grade 2 renal insufficiency at baseline (estimated glomerular filtration rate, 54 mL/min/1.73 m2) developed a grade 3 event. After 6 weeks of receiving study medications, he had received amoxicillin in the context of a dental procedure and continued preenrollment medications (benazepril, telmisartan, and simvastatin). In this context, his estimated glomerular filtration rate decreased to 29 mL/min/1.73 m2 (grade 3 toxicity); however, it improved (grade 2) within 1 week of withdrawing amoxicillin, returned to baseline within 3 weeks, and remained stable thereafter. He received study drugs without interruption. Safety All patients completed treatment, and no grade 4 adverse events or laboratory abnormalities occurred. The most common adverse events were myalgia and hypophosphatemia, and most adverse events were mild (Table 2). Four grade 3 events occurred (increased creatinine levels described above [n=1], hypercholesterolemia [n=1], and hypophosphatemia [n=2]). Table 2. Treatment Discontinuations, Adverse Events, and Laboratory Abnormalities Discussion In this study, we demonstrate that patients with HCV GT-1 who have viral relapse after sofosbuvir plus ribavirin therapy can be successfully re-treated with sofosbuvir plus ledipasvir. Seven (50%) of the patients in this study had advanced liver disease, which has been shown to be associated with relapse after sofosbuvir plus ribavirin therapy (8, 10, 11). In addition to having a high prevalencBackground The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined.

Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial

Background Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of disease cure; however, not enough specialists currently are available to provide care. Objective To determine the efficacy of HCV treatment independently provided by nurse practitioners (NPs), primary care physicians (PCPs), or specialist physicians using DAA therapy. Design Nonrandomized, open-label clinical trial initiated in 2015. (ClinicalTrials.gov: NCT02339038). Setting 13 urban, federally qualified health centers (FQHCs) in the District of Columbia. Patients A referred sample of 600 patients, of whom 96% were black, 69% were male, 82% were treatment naive, and 20% had cirrhosis. Seventy-two percent of the patients had HCV genotype 1a infection. The baseline characteristics of patients seen by each provider type were similar. Intervention Patients were assigned in a nonrandomized but specified manner to receive treatment from 1 of 5 NPs, 5 PCPs, or 6 specialists. All providers underwent an identical 3-hour training session based on guidelines. Patients received treatment with ledipasvir-sofosbuvir, which was provided on site, according to U.S. Food and Drug Administration labeling requirements. Measurements Sustained virologic response (SVR). Results 516 patients achieved SVR, a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR. Limitation Nonrandomized patient distribution; possible referral bias. Conclusion In a real-world cohort of patients at urban FQHCs, HCV treatment administered by nonspecialist providers was as safe and effective as that provided by specialists. Nurse practitioners and PCPs with compact didactic training could substantially expand the availability of community-based providers to escalate HCV therapy, bridging existing gaps in the continuum of care for patients with HCV infection. Primary Funding Source National Institutes of Health and Gilead Sciences.

Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens

BACKGROUND The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. METHODS In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. RESULTS Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. CONCLUSIONS In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants. CLINICAL TRIALS REGISTRATION NCT01805882.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial

BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING Single-center. PATIENTS 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti–Hepatitis C Virus Therapy in Patients With Advanced Liver Disease

BACKGROUND Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION CT01805882.

No Improvement in Hemoglobin A1c Following Hepatitis C Viral Clearance in Patients With and Without HIV

Hepatitis C clearance with directly acting antivirals (DAAs) may be associated with acute decreases in hemoglobin A1c (HbA1c). We prospectively evaluated 251 chronic hepatitis C virus (HCV)-infected subjects (31% human immunodeficiency virus [HIV] positive) pre- and post-DAA therapy (median follow-up 28 months). Changes in HbA1c and glucose were minimal and did not differ by sustained virologic response (SVR), HIV, diabetes, or fibrosis. Following SVR, mean change in HbA1c was -0.022 ± 0.53%; however, total and low-density lipoprotein cholesterol increased significantly. Subjects with HIV had smaller transaminase reductions after SVR. Sustained benefits in glycemia were not identified following HCV clearance irrespective of HIV, diabetes, or fibrosis stage, whereas lipid alterations may warrant further investigation.

HIV/HCV Co-infection: Overcoming Barriers to Treatment

A critical step in the eradication of hepatitis C virus (HCV) infection is access to effective therapy. With the advent of interferon‐free regimens, HCV providers and patients gained hope that the success seen in clinical trials could be translated to the real world. However, the exorbitant cost of the new direct‐acting antivirals limits access to these medications to the general HCV population, especially underserved patients with public insurance. We used a descriptive qualitative approach to detail the measures necessary and challenges faced by an inner‐city nursing team in Washington, DC to obtain the new direct‐acting antivirals. Significant time and dedication on the part of providers and staff was required to assist patients with the process of obtaining direct‐acting antivirals.

A Practical Approach and Model of Care for HCV Treatment With Direct Acting Antivirals in an Urban Setting

Elizabeth Akoth, RN, BSN, MSN, is a Research Lead Specialist, Institute of Human Virology, University of Maryland School of Medicine Baltimore, Maryland, USA, and a Special Volunteer, National Institutes of Health, Bethesda, Maryland, USA. (*Correspondence to: elizabeth.akoth@nih.gov). Chloe Gross, RN, BSN, ACRN, is a Research Lead Specialist, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA, and a Special Volunteer, National Institutes of Health, Bethesda, Maryland, USA. Rachel Silk, RN, BSN, MPH, is a Clinical Nurse Administrator, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA, and a Special Volunteer, National Institutes of Health, Bethesda, Maryland, USA. Elana Rosenthal, MD, is an Assistant Professor, Institute of Human Virology Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland USA, and a Special Volunteer, National Institutes of Health, Bethesda, Maryland, USA. Sarah Kattakuzhy, MD, is an Assistant Professor, Institute of Human Virology Division of Infectious Diseases University of Maryland School of Medicine Baltimore, Maryland, USA, and a Special Volunteer, National Institutes of Health, Bethesda, Maryland, USA. The U.S. Food and Drug Administration’s (FDA) approval of highly efficacious and tolerable directacting antivirals (DAAs) has led to a cure for hepatitis C virus (HCV) in many patients. The American Association for the Study of Liver Diseases (AASLD) and Infectious Disease Society of America (IDSA) guidelines recommended HCV treatment for all patients with chronic HCV regardless of disease stage (AASLD and IDSA, 2016). In contrast, a summary report by the Center for Evidence-Based Policy (2016) showed that many state Medicaid plans restricted treatment to patients with Stage 2 or higher liver disease. In the general population, barriers such as the high cost of DAAs, insurance restrictions, and lack of provider availability have left many without treatment (IDSA and AASLD, 2016). Despite the availability of DAAs, the uptake of these medications has remained low, even in health systems such as the U.S. Veterans Administration, where there were no restrictions to medication acquisition. The Veterans Administration reported that, as of 2013, approximately 174,000 veterans had been diagnosed with HCV infection, but at least 124,000 veterans had yet to be treated (Moon, Green, Berry, & Ioannou, 2016). The District of Columbia (DC) continues to be disproportionately affected by HIV and HCV. As of December 2015, at least 13,391 DC residents were living with HIV, roughly 2% of the Washington, DC,

Retreatment of HCV Genotype-1 with Sofosbuvir and Ledipasvir after Relapse with Sofosbuvir and Ribavirin: A Pilot Study

Context The treatment of hepatitis C virus is changing rapidly with the introduction of interferon-free regimens that include direct-acting antiviral drugs, such as sofosbuvir. Although treatment generally results in sustained viral response, some patients have relapse after initial treatment. Contribution In a small, nonrandomized study, 14 patients who had relapse after treatment with sofosbuvir plus ribavirin were re-treated with sofosbuvir plus ledipasvir for 12 weeks. All patients, including those with advanced liver disease, achieved a sustained virologic response. The combination was generally well-tolerated. Implication Treatment with sofosbuvir plus ledipasvir may be efficacious in patients who have relapse after initial therapy for hepatitis C virus. Larger randomized studies of this promising combination are warranted. The Editors Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma and the leading indication for liver transplantation in Western countries (1, 2). Until recently, HCV treatment consisted of combination therapy with pegylated interferon (IFN) and ribavirin, with the addition of an HCV protease inhibitor (boceprevir or telaprevir) in recent years. In 2013, the U.S. Food and Drug Administration approved sofosbuvir plus ribavirin as the first IFN-free treatment of HCV genotype 2 or 3 and for patients with genotype 1 (GT-1) who are IFN-ineligible (37). Although sofosbuvir (an NS5B inhibitor) plus ribavirin is well-tolerated and effective with sustained virologic response (SVR) rates from 68% to 76% in patients with HCV GT-1 (8, 9), modest rates of relapse in patients with advanced liver disease and transplant recipients have been seen (8, 10, 11). Recent studies using sofosbuvir combined with ledipasvir (an NS5A inhibitor) for 12 weeks demonstrated high SVR rates (95% to 99%) in treatment-naive patients with HCV GT-1 (1215). Ledipasvir has potent antiviral activity against the S282T resistance-associated variant, known to reduce susceptibility to sofosbuvir in vitro (16). As previously reported, 17 of 54 patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study had relapse after treatment (8). We hypothesized that the combination of a second potent direct-acting antiviral agent (DAA) with sofosbuvir could result in SVR, even in patients with relapse after sofosbuvir plus ribavirin therapy and who may harbor the S282T mutation. To test this hypothesis, we re-treated those patients with sofosbuvir plus ledipasvir for 12 weeks. Methods Design Overview All patients who had relapse after 24 weeks of treatment with sofosbuvir plus ribavirin in the NIAID SPARE study (8) were offered re-treatment with sofosbuvir plus ledipasvir in the ongoing, phase 2a, open-label NIAID SYNERGY study (ClinicalTrials.gov: NCT01805882). Of the 17 eligible patients, 3 did not participate in the study. Fourteen patients enrolled and were treated with 400 mg of sofosbuvir and 90 mg of ledipasvir, administered daily as a single combination tablet, for 12 weeks. Setting and Patients The trial was conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and at community clinics that are part of the District of Columbia Partnership for HIV/AIDS Progress in Washington, DC. Written informed consent, which was approved by the NIAID Institutional Review Board, was obtained from all study patients. Eligibility criteria included documented HCV GT-1 infection and relapse in the NIAID SPARE study (8). Liver fibrosis stage was determined by biopsy within 3 years of enrollment in the NIAID SPARE study. The study was approved by the NIAID Institutional Review Board. It was conducted in adherence to the Good Clinical Practice guidelines and with regulatory requirements consistent with the Declaration of Helsinki. Outcomes and Follow-up Efficacy Assessments Plasma HCV RNA levels were measured using the Abbott RealTime HCV assay, with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL, or the Roche Cobas TaqMan HCV assay, version 2.0, with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL. Safety Assessments Patients were closely monitored for adverse events. Clinical laboratory results were assessed while receiving therapy (4, 8, and 12 weeks) and afterward (2, 4, 8, and 12 weeks after treatment). Adverse events were graded from 1 (mild) to 4 (severe), according to the NIAID Division of AIDS Toxicity Table (version 1.0). Interleukin-28B Genotyping Interleukin-28B genotype (rs12979860) was determined as previously described (8). Clinical End Points The primary end point was the proportion of patients with unquantifiable plasma HCV viral load 12 weeks after treatment completion. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes. Statistical Analysis Primary safety and efficacy data were analyzed by intention-to-treat (all patients who initiated study medication). Missing virologic data were imputed if data from preceding and succeeding time points were obtained. Baseline demographics were described using frequency statistics. Comparisons were calculated using either nonparametric tests or t tests with GraphPad Prism, version 6.0 (GraphPad Software). Role of the Funding Source This study was funded in part by the National Cancer Institute, the intramural programs of the NIH Clinical Center and NIAID, and a Collaborative Research and Development Agreement between the NIH and Gilead Sciences. The study sponsor was the Regulatory Compliance and Human Participants Protection Branch of the NIAID. The sponsor reviewed the study and provided oversight. However, it did not play a role in designing the study; collecting, analyzing, or interpreting the data; or the preparation, review, approval, or submission of the manuscript for publication. All study medications were provided by Gilead Sciences, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients Most study patients were black men with an unfavorable interleukin-28B non-CC genotype (Table 1). There was a high representation of patients with HCV GT-1a infection, increased baseline HCV viral load (>800000 IU/mL), increased body mass index (>30 kg/m2), and advanced liver disease (Knodell Histology Activity Index score of 3 or 4) (17). Table 1. Baseline Characteristics of Study Patients Presence of S282T Mutation At the time of relapse after sofosbuvir plus ribavirin treatment in the SPARE trial, 13 of 14 patients had wild-type virus by population sequencing (Supplement). The 1 exception achieved unquantifiable HCV RNA levels by week 2 of therapy in SPARE and the virus remained undetectable through the end of treatment. He missed his visit at 26 weeks (2 weeks after treatment), but at 28 weeks (4 weeks after treatment), his HCV viral load was 374 IU/mL and the S282T mutation was readily detected by population sequencing. By 36 weeks (12 weeks after treatment), his HCV viral load was 81286 IU/mL and the S282T mutation was no longer detectable. He initiated sofosbuvir plus ledipasvir treatment 50 weeks after relapse. Supplement. HCV Resistance Mutations Virologic Response Each of the 14 patients treated with sofosbuvir plus ledipasvir had HCV RNA levels below the lower limit of quantification by 4 weeks (Roche Cobas TaqMan HCV Assay, version 2.0), which was maintained through the end of treatment (12 weeks). All patients achieved SVR 12 weeks after completion of treatment. Changes in Hemoglobin Levels No significant change in hemoglobin levels during sofosbuvir plus ledipasvir treatment was seen, in contrast to the decrease seen with sofosbuvir plus ribavirin. The mean hemoglobin level change was 0.07 g/L versus 11.70 g/L at 4 weeks (P=0.01), 0.5 g/L versus 12.6 g/L at 8 weeks (P=0.01), and 3.1 g/L versus 12.1 g/L at 12 weeks (P=0.06) with sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin, respectively. No participant had a decrease in hemoglobin level of 15.0 g/L or greater with sofosbuvir plus ledipasvir compared with 8 of 14 (57%) with sofosbuvir plus ribavirin. Changes in Renal Function Renal variables did not change significantly over the course of treatment, although a single participant with grade 2 renal insufficiency at baseline (estimated glomerular filtration rate, 54 mL/min/1.73 m2) developed a grade 3 event. After 6 weeks of receiving study medications, he had received amoxicillin in the context of a dental procedure and continued preenrollment medications (benazepril, telmisartan, and simvastatin). In this context, his estimated glomerular filtration rate decreased to 29 mL/min/1.73 m2 (grade 3 toxicity); however, it improved (grade 2) within 1 week of withdrawing amoxicillin, returned to baseline within 3 weeks, and remained stable thereafter. He received study drugs without interruption. Safety All patients completed treatment, and no grade 4 adverse events or laboratory abnormalities occurred. The most common adverse events were myalgia and hypophosphatemia, and most adverse events were mild (Table 2). Four grade 3 events occurred (increased creatinine levels described above [n=1], hypercholesterolemia [n=1], and hypophosphatemia [n=2]). Table 2. Treatment Discontinuations, Adverse Events, and Laboratory Abnormalities Discussion In this study, we demonstrate that patients with HCV GT-1 who have viral relapse after sofosbuvir plus ribavirin therapy can be successfully re-treated with sofosbuvir plus ledipasvir. Seven (50%) of the patients in this study had advanced liver disease, which has been shown to be associated with relapse after sofosbuvir plus ribavirin therapy (8, 10, 11). In addition to having a high prevalencBackground The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined.

P-B4 Predictors of sustained viral response to 4–6 week duration therapy with Ledipasvir + Sofosbuvir + Gs-9451 +/− Gs-9669 in early and advanced fibrosis (Nih-Ihv synergy trial)

Background:Directly-acting antivirals (DAA) have streamlined the treatment of hepatitis C, however, limited data exists to define minimum duration of therapy. The aim of this study is to further elucidate treatment length and predictive factors of response in early and advanced fibrosis patients treated with combination DAA therapy. METHODS: In this single- center, open label, phase 2a trial, 100 HCV monoinfected participants were sequentially enrolled into three treatment arms. Treatment naive (TN) patients with F0–F2 fibrosis received LDV/SOF+GS-9451 (n = 25) or LDV/SOF+GS-9451+GS-9669 (n = 25) for 4 weeks. Patients with F3–F4 fibrosis received LDV/SOF+GS-9451 for 6 weeks [n = 25 TN & n = 25 IFN-Treatment Experienced (TE)]. HCV RNA was measured using Roche COBAS Taqman v2.0 assay with a LLOQ of 25 IU/mL. Primary endpoint was sustained virologic response defined as HCV RNA BLLOQ 12 weeks post-treatment (SVR12). Pretreatment serum samples were analyzed for resistance-associated variants (RAV) using the Illumina deep sequencing platform. Results:In the early fibrosis cohort, 10/25 (40%) patients receiving LDV/SOF+GS-9451 achieved SVR12, and 5/25 (20%) receiving LDV/SOF+GS-9451+GS-9669 achieved SVR12, with one patient lost to follow up. Baseline HCV VL >6 million was a predictor of relapse in univariate analysis and no patient with RAVs conferring >20 fold resistance achieved SVR. In the advanced fibrosis cohort, 37/50 (74%) achieved SVR, with no correlates of response on univariate analysis. TN (68%) and TE (80%) patients had no significant difference in response rate. In the TN cohort, 2 patients were lost to follow up. Conclusions:In this cohort study, combination DAA treatment resulted in moderate rates of SVR when given for six weeks, but was not effective for four weeks. Patients with high baseline VL and resistance mutants are likely to relapse with 4 week therapy. Larger studies are required to further characterize the biologic correlates in the unique group of responders to short duration therapy.