Benjamin Emmanuel

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.

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.

Evaluating the Causal Link Between Malaria Infection and Endemic Burkitt Lymphoma in Northern Uganda: A Mendelian Randomization Study

Background Plasmodium falciparum (Pf) malaria infection is suspected to cause endemic Burkitt Lymphoma (eBL), but the evidence remains unsettled. An inverse relationship between sickle cell trait (SCT) and eBL, which supports that between malaria and eBL, has been reported before, but in small studies with low power. We investigated this hypothesis in children in a population-based study in northern Uganda using Mendelian Randomization. Methods Malaria-related polymorphisms (SCT, IL10, IL1A, CD36, SEMA3C, and IFNAR1) were genotyped in 202 eBL cases and 624 controls enrolled during 2010–2015. We modeled associations between genotypes and eBL or malaria using logistic regression. Findings SCT was associated with decreased risk of eBL (adjusted odds ratio [OR] 0·37, 95% CI 0·21–0·66; p = 0·0003). Decreased risk of eBL was associated with IL10 rs1800896-CT (OR 0·73, 95% CI 0·50–1·07) and -CC genotypes (OR 0·53, 95% CI 0·29–0·95, ptrend = 0·019); IL1A rs2856838-AG (OR 0·56, 95% CI 0·39–0·81) and -AA genotype (OR 0·50, 95% CI 0·28–1·01, ptrend = 0·0016); and SEMA3C rs4461841-CT or -CC genotypes (OR 0·57, 95% CI 0·35–0·93, p = 0·0193). SCT and IL10 rs1800896, IL1A rs2856838, but not SEMA3C rs4461841, polymorphisms were associated with decreased risk of malaria in the controls. Interpretation Our results support a causal effect of malaria infection on eBL.

Racial disparity in all-cause mortality among hepatitis C virus-infected individuals in a general US population, NHANES III.

There are few long‐term nationally representative studies of all‐cause mortality among those infected with hepatitis C virus (HCV). When an additional 5 years of data were made publicly available in 2015, the Third National Health and Nutrition Examination Survey Linked Mortality File became the longest nationally representative study in the United States. Our objective was to update the estimated HCV‐associated all‐cause mortality in the general US population and determine any differences by sex, age and race/ethnicity. HCV status was assessed in 9117 nationally representative adults aged 18‐59 years from 1988 to 1994, and mortality follow‐up of the same individuals was completed through 2011 and made publicly available in 2015. There were 930 deaths over a median follow‐up of 19.8 years. After adjusting for all covariate risk factors, chronic HCV had 2.63 times (95% CI: 1.59‐4.37; P=.0002) higher all‐cause mortality rate ratio (MRR) compared with being HCV negative. All‐cause MRR was stratified by sex, age and race/ethnicity. Only race/ethnicity was a significant effect modifier of MRR (P<.0001) as the highest MRR of chronic HCV compared to HCV negative was 7.48 (95% CI: 2.15‐26.10, P=.001) among Mexican Americans, 2.67 (95% CI: 2.67‐5.56, P=.009) among non‐Hispanic Whites and 2.02 (95% CI: 1.20‐3.40, P=.007) among non‐Hispanic Blacks. Racial disparity was seen in the all‐cause mortality as Mexican Americans with chronic HCV had approximately seven times higher mortality rate than HCV‐negative individuals. This suggests that these at‐risk individuals should be targeted for HCV screening and treatment, given the availability of new highly effective HCV therapies.

Shortening the duration of therapy for chronic hepatitis C infection.

Combination direct-acting antiviral therapy of 8-24 weeks is highly effective for the treatment of chronic hepatitis C infection. However, shortening the treatment duration to less than 8 weeks could potentially reduce overall treatment costs and improve adherence. Here we explore the arguments for and against the development of short-duration regimens and existing data on treatment for 6 weeks or less among patients with chronic hepatitis C virus genotype 1 infection. Additionally, we identify potential predictors of response to short-course combination therapies with direct-acting antiviral drugs that might be explored in future clinical trials.

Decline of cellular activation in non-B cells after rituximab treatment in hepatitis C-associated mixed cryoglobulinemia vasculitis

Mixed cryoglobulinemic vasculitis is associated with the monoclonal expansion of pathognomonic B cells in chronic hepatitis C. Recently, treatment with B‐cell depletion, including rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from the active disease. We investigated whether B‐cell depletion therapy has an impact on activation of non‐B cells in the periphery. Results demonstrated that B‐cell depletion therapy is associated with a statistically significant decline in activated T cells, from pretherapy to follow‐up while on rituximab therapy: CD4+ CD38+ HLA‐DR+ (DR+), CD8+ CD38, CD8+ CD38+ DR+, and CD8+ DR+. Birmingham Vasculitis Activity Score and cryoglobulin had a strong correlation coefficient (R) of 0.72 (P=.0005), while cryoglobulin showed moderate correlation with CD8+ DR+ (R=.61), CD3+ CD38+ DR+ (R=.57), CD3+ DR+ (R=.50), CD4+ CD38+ DR+ (R=.53), CD4+ DR+ (R=.52), and CD8+ CD38+ DR+ (R=.67). These results suggest B‐cell expansion has a direct and indirect effect on the pathogenesis of Hepatitis C‐associated mixed cryoglobulinemic vasculitis.

Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis

Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV‐specific T cell phenotype and function. Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375 mg/m2) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme‐Linked Immunospot assay, the number of activated and tissue‐like B cells and number of T cells expressing Programmed cell death protein 1 (PD‐1), T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), and multiple cytokines were measured before and after rituximab therapy. B cell depletion therapy is associated with a significant (P < 0.0001) decline in peripheral T cells with exhaustive phenotype, from pre‐therapy to post‐therapy‐of rituximab (mean ± standard error): CD4+ (16.9 ± 0.9% to 8.9 ± 1.0%) and CD8+ (6.8 ± 0.6% to 3.0 ± 0.5%) T cells expressing PD‐1 and CD4+ (11.0 ± 1.0% to 6.1 ± 0.8%) and CD8+ (12.7 ± 0.7% to 6.4 ± 0.4%) T cells expressing TIM‐3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN‐γ (4.55 ± 0.3 to 9.6 ± 1.0 IFN‐γ/106 PBMCs, P < 0.0001), and more than one cytokine (1.3 ± 0.1% to 3.8 ± 0.2%, P < 0.0001) after therapy compared to pre‐therapy. B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis.

Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis

B cell depletion therapy using rituximab has been shown to be effective in achieving remission in patients with HCV-mixed cryoglobulinemic (MC) vasculitis. Previously, we have demonstrated abnormalities in peripheral immune cells involving neutrophils, chemotaxis, and innate immune activation among patients with HCV-MC vasculitis when compared to HCV patients without vasculitis. In this study, we evaluated the effect of B cell depletion therapy on transcriptional profiles of peripheral blood mononuclear cells before and after riruximab therapy, in order to unravel the pathogenic mechanism involved in HCV-MC vasculitis induced by abnormal B cell proliferation. DNA microarray analysis was performed using RNA from PBMCs from seven patients with HCV-MC vasculitis and seven normal volunteers. DNA was hybridized to Affymetrix U133A chips. After normalization, differentially expressed gene list with treatment was generated using partitional clustering. RT-PCR, flow cytometry, and enzyme immunoassay (EIA) was used to validate DNA microarray findings. Differentially expressed genes included B cells and non-B cell genes. Validation of genes using purified cell subsets demonstrated distinct effect of B cell depletion therapy on non-B cells, such as monocytes, T cells, and NK cells. Notably, B lymphocyte stimulator (BLyS) levels were persistently elevated in patients who subsequently relapsed. In conclusion, pathogenesis of HCV-MC vasculitis is mediated by abnormal proliferation of B cells, driven by BLyS, leading to significant effects on non-B cells in mediating symptomatology. Future therapeutics using a combination approach of B cell depletion and proliferation may be desired to achieve long-term remission.

P-B26 Changes in plasma BLyS levels in patients with HCV mixed cryoglobulinemic vasculitis during treatment with Rituximab

Background:Mixed Cryoglobulinemic Vasculitis (MC) is a known complication of chronic hepatitis C virus (HCV) infection, characterized by monoclonal expansion of IgM secreting B cells. B-lymphocyte Stimulator (BLyS), a member of the tumor-necrosis-factor super family of ligands, is an essential in vivo regulator of B cell homeostasis. High levels of BLyS have been observed in several autoimmune B cell mediated diseases. In this study, we evaluated plasma BLyS levels in patients with HCV-MC before, during, and after treatment with rituximab (RTX) compared with normal volunteers (NV). Methods:We treated patients with HCV-MC with 4 cycles of IV RTX (375 mg/m2) and followed for response for an additional year. Plasma samples were tested for the levels of BLyS using ELISA from patients with HCV-MC (N = 14) before (day 0), during RTX treatment (month 1, 4), during full recovery (month 8), and from normal volunteers (NV) (N = 8). ANOVA was used for statistical comparisons on the levels of BLyS between the different groups. Result:Plasma BLyS levels were elevated among patients with HCV-MC (Mean 1.12 ± 0.4 ng/mL) when compared with NV (Mean 0.67 ± 0.1 ng/mL). Among patients with HCV- MC, plasma BLyS levels increased at one month post treatment with RTX (Mean 3.6 ± 0.6 ng/mL, P = 0.03). In patients with HCV-MC, BLyS levels were inversely correlated with B cell counts (r = −0.81, p2 ng/mL at month 8 in 4/6 patients who either had a relapse or did not achieve remission. Conclusions:BLyS levels are elevated in patients with B cell autoimmunity, such as HCV-MC. In patients with HCV-MC, persistently high levels of BLyS were observed in those who relapsed following RTX, thus suggesting a pathogenic role for BLyS in HCV-MC. These results provide a rationale for targeting BLyS, along with B cell depletion therapies, as a novel approach for the management of HCV-MC.