Chloe Gross

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.

Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir.

Objective:As the treatment of hepatitis C virus (HCV) infection has evolved to directly acting antiviral agents, the impact of these directly acting antiviral-only regimens on improving adherence to HCV treatment in HIV/HCV coinfected populations has not been evaluated. The study compared adherence to ledipasvir/sofosbuvir (LDV/SOF) in HCV monoinfected and HIV/HCV coinfected individuals. Design:Adherence was measured from participants in two phase 2 open-label studies (NCT01805882 and NCT01878799). Methods:HCV treatment-naive, genotype 1 study individuals [HCV monoinfected participants (N = 20) and HIV/HCV coinfected participants, antiretroviral untreated (N = 13) or on combination antiretroviral therapy (N = 37)] were treated with LDV (90 mg) and SOF (400 mg) administered as one tablet once daily for 12 weeks. Adherence was measured using three tools: medication event monitoring system cap, pill count, and patient report. Results:Participants were predominately African American (83%) and male (73%), with a median age of 59 years. Participants had prompt HCV viral load decline and high adherence rates (97 ± 0.5% by medication event monitoring system). Participant adherence decreased significantly from early (baseline week 4) as compared with late (weeks 8–12) in therapy in all three groups – HCV monoinfected (P = 0.01), HIV/HCV antiretroviral untreated (P = 0.02), and HIV/HCV antiretroviral treated participants (P = 0.01). Conclusion:Adherence to LDV/SOF in this urban population was high and comparable between HCV monoinfected and HIV/HCV coinfected participants regardless of antiretroviral use.

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,

Longterm Evaluation of Hemoglobin A1c Following Hepatitis C Therapy in Patients with and without HIV Co-infection

Abstract Background Historically, eradication of HCV with interferon-based treatments was linked with decreased incidence of diabetes. While viral clearance with direct acting agents (DAAs) may be associated with acute decreases in fasting glucose levels and hemoglobin A1c (HbA1c), there remains a need for larger prospective studies to address the longterm impact of sustained viral response (SVR) achieved with DAAs on glucose metabolism. Methods Prospective longitudinal cohort study of 251 subjects with chronic HCV (100% genotype 1a/b, 31% HIV+, 17% diabetes) evaluated pre- and post-DAA therapy with median follow-up of 28 mos. Change in HbA1c, glucose, lipid and transaminase levels were compared based on SVR, HIV, diabetes status and fibrosis stage. Results There was no difference in change in HbA1c between subjects who achieved SVR (n = 241) compared with those who did not. Mean change in HbA1c did not differ from zero (−0.022 ± 0.53%) for those with SVR. Further, when subjects were grouped based on HIV, diabetes or fibrosis stage, there were no significant differences in changes in HbA1c or glucose following SVR. Subjects with HIV had smaller reductions in transaminase values (change ALT −33.3 ± 51 IU/L HIV+ vs. −47.8 ± 45 IU/L HIV-, P = 0.0007). Following SVR, total and LDL cholesterol increased (P = 0.0002 and P = 0.0003, respectively) whereas triglyceride levels decreased (P = 0.008). A greater proportion of subjects (7%) started or increased medication therapy for diabetes following SVR compared with the percentage who decreased diabetes therapy (3%). There was a statistically significant positive correlation between change in BMI and change in HbA1c (r=0.17, P = 0.006). Conclusion The current study failed to identify sustained benefits in glucose or HbA1c in HCV treated patients, irrespective of HIV, diabetes or fibrosis stage. HIV infection blunted improvements in transaminase levels related to SVR. While HbA1c did not improve with HCV clearance, alterations in lipids were identified that warrant further investigation. Disclosures C. Gross, Merck: stock holder, Own stock; Pfizer: stock holder, Own stock; JohnsonandJohnson: stock holder, Own stock

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.